complaint for patent infringement the parties · pharmaceuticals is a “truly . . . global...

UNITED STATES DISTRICT COURT

DISTRICT OF NEW JERSEY OTSUKA PHARMACEUTICAL CO., LTD., Plaintiff, v. MACLEODS PHARMACEUTICALS LTD. AND MACLEODS PHARMA USA, INC., Defendants.

Civil Action No.:

COMPLAINT FOR PATENT INFRINGEMENT

Plaintiff Otsuka Pharmaceutical Co., Ltd. (“Otsuka”), by way of Complaint against

Defendants Macleods Pharmaceuticals Ltd. (“Macleods Pharmaceuticals”) and Macleods

Pharma USA, Inc. (“Macleods USA”) (collectively “Macleods”), alleges as follows:

THE PARTIES

1. Otsuka is a corporation organized and existing under the laws of Japan with its

corporate headquarters at 2-9 Kanda Tsukasa-machi, Chiyoda-ku, Tokyo, 101-8535, Japan.

Otsuka is engaged in the research, development, manufacture and sale of pharmaceutical

products.

2. Upon information and belief, Macleods Pharmaceuticals is a private corporation

organized and existing under the laws of India, having a place of business at Atlanta Arcade,

Marol Church Road, Andheri (East), Mumbai, India 400059.

3. Upon information and belief, Macleods USA is a private corporation organized

and existing under the laws of the State of Delaware, having its headquarters and principal place

Case 1:16-cv-05400-JBS-KMW Document 1 Filed 09/02/16 of 7 PageID: 1

2

of business at 666 Plainsboro Road, Building 200, Suite 230, Plainsboro, NJ 08536. Upon

information and belief, Macleods USA is a wholly-owned subsidiary of Macleods

Pharmaceuticals.

NATURE OF THE ACTION

4. This is an action for infringement of U.S. Patent No. 9,359,302 (“the ’302

patent”) arising under the United States patent laws, Title 35, United States Code, § 100 et seq.,

including 35 U.S.C. §§ 271 and 281. This action relates to Macleods Pharmaceuticals filing of

an Abbreviated New Drug Application (“ANDA”) under Section 505(j) of the Federal Food,

Drug and Cosmetic Act (“the Act”), 21 U.S.C. § 355(j), seeking U.S. Food and Drug

Administration (“FDA”) approval to manufacture, use, sell, offer to sell and import generic

pharmaceutical products (“Macleods’ generic products”) prior to the expiration of the asserted

patent.

JURISDICTION AND VENUE

5. This Court has subject matter jurisdiction under 28 U.S.C. §§ 1331 and 1338(a).

6. This Court has jurisdiction over Macleods Pharmaceuticals. Upon information

and belief, Macleods Pharmaceuticals is in the business of manufacturing, marketing, importing

and selling pharmaceutical drug products, including generic drug products. Upon information

and belief, Macleods Pharmaceuticals, directly or indirectly, manufactures, imports, markets and

sells generic drugs throughout the United States and in this judicial district. Upon information

and belief, Macleods Pharmaceuticals purposefully has conducted and continues to conduct

business, directly or indirectly, in this judicial district, and this judicial district is a likely

destination of Macleods’ generic products. Upon information and belief, Macleods

Pharmaceuticals is a “truly . . . global pharmaceutical company.” See


3

http://www.macleodspharma.com/default.asp. Upon information and belief, Macleods

Pharmaceuticals’ website states that “Macleods has received FDA approval on 9 [ANDAs] and

has another 60 filed and awaiting approval.” See

http://www.macleodspharma.com/UnitedStates.asp.

7. This Court has jurisdiction over Macleods USA. Upon information and belief,

Macleods USA is in the business of manufacturing, marketing, importing and selling

pharmaceutical drug products, including generic drug products. Upon information and belief,

Macleods USA, directly or indirectly, manufactures, imports, markets and sells generic drug

products throughout the United States and in this judicial district. Upon information and belief,

Macleods USA is registered as a wholesaler in the State of New Jersey (No. 5004370). See New

Jersey Registration and Verification, at

http://web.doh.state.nj.us/apps2FoodDrugLicense/fdList.aspx.

8. Upon information and belief, Macleods Pharmaceuticals and Macleods USA

operate as a single integrated business with respect to the regulatory approval, manufacturing,

marketing, sale and distribution of generic pharmaceutical products throughout the United States

including in this judicial district. Upon information and belief, Macleods Pharmaceuticals is “a

vertically integrated global pharmaceutical company” with “more than 10,000 professionally

qualified employees across the globe.” See http://www.macleodspharma.com/default.asp.

9. Venue is proper in this judicial district under 28 U.S.C. §§ 1391(b) and (c), and

§ l400(b).

FIRST COUNT FOR PATENT INFRINGEMENT


4

10. The U.S. Patent and Trademark Office (“PTO”) issued the ’302 patent on June 7,

2016, entitled “Low Hygroscopic Aripiprazole Drug Substance and Processes for the Preparation

Thereof.” A copy of the ’302 patent is attached as Exhibit A.

11. Otsuka is the owner of the ’302 patent by virtue of assignment.

12. The ’302 patent expires on September 25, 2022, excluding any pediatric

exclusivity.

13. The ’302 patent is directed to and claims, inter alia, aripiprazole crystals,

pharmaceutical compositions and methods of treatment.

14. Otsuka is the holder of New Drug Application (“NDA”) No. 21-436 for

aripiprazole tablets, which the FDA approved on November 15, 2002.

15. Otsuka lists the ’302 patent in Approved Drug Products with Therapeutic

Equivalence Evaluations (“the Orange Book”) for NDA No. 21-436.

16. Otsuka markets aripiprazole tablets in the United States under the trademark

Abilify®.

17. Upon information and belief, Macleods Pharmaceuticals submitted ANDA No.

204111 to the FDA, under Section 505(j) of the Act, 21 U.S.C. § 355(j), seeking approval to

manufacture, use, import, offer to sell and sell Macleods’ generic products in the United States.

18. Otsuka received a letter from Macleods Pharmaceuticals dated July 21, 2016,

purporting to include a Notice of Certification for ANDA No. 204111 under 21 U.S.C.

§ 355(j)(2)(B)(ii) and 21 C.F.R. § 314.95 (“Macleods Pharmaceuticals’ 204111 letter”) as to

the ’302 patent.


5

19. Macleods Pharmaceuticals’ 204111 letter alleges that it seeks “to obtain approval

to engage in the commercial manufacture, use, importation, offer for sale and sale of Macleods’

2 mg, 5 mg, 10 mg, 15 mg, 20 mg and 30 mg of aripiprazole tablets.”

20. Upon information and belief, Macleods’ generic products will, if approved and

marketed, infringe at least one claim of the ’302 patent.

21. Upon information and belief, under 35 U.S.C. § 271(e)(2)(A), Macleods

Pharmaceuticals has infringed at least one claim of the ’302 patent by submitting, or causing to

be submitted to the FDA, ANDA No. 204111 seeking approval to manufacture, use, import,

offer to sell and sell Macleods’ generic products before the expiration date of the ’302 patent.

22. Upon information and belief, Macleods Pharmaceuticals’ actions relating to

ANDA No. 204111 complained of herein were done with the cooperation, participation and

assistance, and for the benefit, of Macleods Pharmaceuticals and Macleods USA.

WHEREFORE, Plaintiff Otsuka respectfully requests that the Court enter judgment in its favor

and against Macleods on the patent infringement claims set forth above and respectfully requests

that this Court:

1) enter judgment that, under 35 U.S.C. § 271(e)(2)(A), Macleods has infringed at

least one claim of the ’302 patent through Macleods Pharmaceuticals’ submission

of ANDA No. 204111 to the FDA to obtain approval to manufacture, use, import,

offer to sell and sell Macleods’ generic products in the United States before the

expiration of the ’302 patent;

2) order that the effective date of any approval by the FDA of Macleods’ generic

products be a date that is not earlier than the expiration of the ’302 patent, or such

later date as the Court may determine;


6

3) enjoin Macleods from the manufacture, use, import, offer for sale and sale of

Macleods’ generic products until the expiration of the ’302 patent, or such later date

as the Court may determine;

4) enjoin Macleods and all persons acting in concert with Macleods from seeking,

obtaining or maintaining approval of Macleods Pharmaceuticals’ ANDA No.

204111 until expiration of the ’302 patent;

5) declare this to be an exceptional case under 35 U.S.C. §§ 285 and 271(e)(4) and

award Otsuka costs, expenses and disbursements in this action, including

reasonable attorney fees; and

6) award Otsuka such further and additional relief as this Court deems just and proper.

Respectfully submitted,

s/Melissa A. Chuderewicz Melissa A. Chuderewicz [email protected] PEPPER HAMILTON LLP Suite 400 301 Carnegie Center Princeton, New Jersey 08543 (609) 452-0808 Attorney for Plaintiff

Otsuka Pharmaceutical Co., Ltd.

Dated: September 2, 2016

Of counsel:

James B. Monroe Paul W. Browning Eric J. Fues Denise Main Jeffrey A. Freeman


7

FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, LLP 901 New York Avenue, N.W. Washington, DC 20001-4413 (202) 408-4000


CIVIL COVER SHEET

I. (a) PLAINTIFFS DEFENDANTS

(b)

(c)

II. BASIS OF JURISDICTION III. CITIZENSHIP OF PRINCIPAL PARTIES

PTF DEF PTF DEF

IV. NATURE OF SUITCONTRACT TORTS FORFEITURE/PENALTY BANKRUPTCY OTHER STATUTES

PERSONAL INJURY PERSONAL INJURY

PROPERTY RIGHTS

LABOR SOCIAL SECURITY PERSONAL PROPERTY

REAL PROPERTY CIVIL RIGHTS PRISONER PETITIONS FEDERAL TAX SUITSHabeas Corpus:

IMMIGRATIONOther:

V. ORIGIN

VI. CAUSE OF ACTION(Do not cite jurisdictional statutes unless diversity

VII. REQUESTED IN COMPLAINT:

CLASS ACTION DEMAND $JURY DEMAND:

VIII. RELATED CASE(S) IF ANY

FOR OFFICE USE ONLY

Otsuka Pharmaceutical Co., Ltd.

Foreign

Melissa A. Chuderewicz, Pepper Hamilton LLP, Suite 400, 301 CarnegieCenter, Princeton, New Jersey 08453-5276,[email protected], 609-951-4118

Macleods Pharmaceuticals Ltd. and Macleods Pharma USA, Inc.

Foreign

35 U.S.C. Section 271 and Section 281

Patent Infringement

Honorable Jerome B. Simandle See attached list.

09/02/2016 s/Melissa A. Chuderewicz

Case 1:16-cv-05400-JBS-KMW Document 1-1 Filed 09/02/16 Page 1 of 2 PageID: 8

VIII. Related Case(s) If Any Judge: Honorable Jerome B. Simandle Docket Number: 14-cv-01078 14-cv-02982 14-cv-03168 14-cv-03306 14-cv-03996 14-cv-04508 14-cv-04671 14-cv-05537 14-cv-05876 14-cv-07105 14-cv-07252 14-cv-08074 14-cv-08077 15-cv-00161 15-cv-01585 15-cv-05109 15-cv-06353 15-cv-08305 16-cv-00405 16-cv-02475 16-cv-05288


#40656248 v1 (134003.28)

Melissa A. Chuderewicz PEPPER HAMILTON LLP Suite 400 301 Carnegie Center Princeton, NJ 08543-5276 (609) 452-0808 - Phone (609) 452-1147 - Facsimile Attorney for Plaintiff Otsuka Pharmaceutical Co., Ltd.

UNITED STATES DISTRICT COURT DISTRICT OF NEW JERSEY

OTSUKA PHARMACEUTICAL CO., LTD., Plaintiff, v. MACLEODS PHARMACEUTICALS LTD. AND MACLEODS PHARMA USA, INC., Defendants.

Civil Action No.:

CERTIFICATION PURSUANT TO L.CIV.R. 11.2

The undersigned hereby certifies that the matters in this case are related to: Otsuka

Pharmaceutical Co., Ltd. v. Torrent Pharmaceuticals Limited, Torrent Pharma Inc. and Hetero

Labs Limited, Civil Action No. 14-1078; Otsuka Pharmaceutical Co., Ltd. v. Alembic

Pharmaceuticals Limited, Civil Action No. 14-2982; Otsuka Pharmaceutical Co., Ltd. v. Zydus

Pharmaceuticals USA Inc. and Cadila Healthcare Limited, Civil Action No. 14-3168; Otsuka

Pharmaceutical Co., Ltd. v. Aurobindo Pharma Limited, Aurobindo Pharma USA, Inc. and

Aurolife Pharma LLC, Civil Action No. 14-3306; Otsuka Pharmaceutical Co., Ltd. v. Intas

Pharmaceuticals Limited, Accord Healthcare, Inc. and Hetero Labs Limited, Civil Action No.

14-3996; Otsuka Pharmaceutical Co., Ltd. v. Mylan Inc. and Mylan Pharmaceuticals Inc., Civil


2 #40656248 v1 (134003.28)

Action No. 14-4508; Otsuka Pharmaceutical Co., Ltd. v. Torrent Pharmaceuticals Limited,

Torrent Pharma Inc. and Hetero Labs Limited, Civil Action No. 14-4671; Otsuka

Pharmaceutical Co., Ltd. v. Huahai US Inc., Prinston Pharmaceutical Inc. and Solco Healthcare

U.S. LLC, Civil Action No. 14-5537; Otsuka Pharmaceutical Co., Ltd. v. Ajanta Pharma

Limited, Ajanta Pharma USA Inc. and Aurobindo Pharma Limited, Civil Action No. 14-5876;

Otsuka Pharmaceutical Co., Ltd. v. Intas Pharmaceuticals Limited, Accord Healthcare, Inc. and

Hetero Labs Limited, Civil Action No. 14-6158; Otsuka Pharmaceutical Co., Ltd. v. Otsuka

Pharmaceutical Co., Ltd. v. Aurobindo Pharma Limited, Aurobindo Pharma USA, Inc. and

Aurolife Pharma LLC, Civil Action No. 14-6890; Otsuka Pharmaceutical Co., Ltd. v. Lupin

Limited, Lupin Atlantis Holding SA, Lupin Pharmaceuticals, Inc. and Hetero Labs Limited, Civil

Action No. 14-7105; Otsuka Pharmaceutical Co., Ltd. v. Zydus Pharmaceuticals USA Inc. and

Cadila Healthcare Limited, Civil Action No. 14-7252; Otsuka Pharmaceutical Co., Ltd. v.

Alembic Pharmaceuticals Limited, Civil Action No. 14-7405; Otsuka Pharmaceutical Co., Ltd.

v. Apotex Corp., Apotex Inc. and Hetero Labs Limited, Civil Action No. 14-8074; Otsuka

Pharmaceutical Co., Ltd. v. ScieGen Pharmaceuticals Inc., Bactolac Pharmaceutical, Inc. and

Hetero Labs Limited, Civil Action No. 14-8077; Otsuka Pharmaceutical Co., Ltd. v. Hetero

Drugs Limited, Hetero Labs Limited and Hetero USA, Inc., Civil Action No. 15-161; Otsuka

Pharmaceutical Co., Ltd. v. Amneal Pharmaceuticals LLC and Amneal Pharmaceuticals India

Pvt. Ltd., Civil Action No. 15-1585; Otsuka Pharmaceutical Co., Ltd. v. Macleods

Pharmaceuticals Ltd. and Macleods Pharma USA, Inc., Civil Action No. 15-5109; Otsuka

Pharmaceutical Co., Ltd. v. Stason Pharmaceuticals Inc., Zhejiang Jinhua Conba Bio-Pharm

Co., Ltd., Tai Heng Industry Co., Ltd. and Breckenridge Pharmaceutical, Inc., Civil Action No.

15-6353; Otsuka Pharmaceutical Co., Ltd. v. Alkem Laboratories Limited, Civil Action No. 15-


3 #40656248 v1 (134003.28)

8305; Otsuka Pharmaceutical Co., Ltd. v. Orchid Pharma Ltd., Orchid Healthcare, Orchid

Pharma, Inc. and Orgenus Pharma Inc., Civil Action No. 16-405; Otsuka Pharmaceutical Co.,

Ltd. v. Orchid Pharma Ltd., Orchid Healthcare, Orchid Pharma, Inc. and Orgenus Pharma Inc.,

Civil Action No. 16-424; and Otsuka Pharmaceutical Co., Ltd. v. Ajanta Pharma Limited and

Ajanta Pharma USA Inc., Civil Action No. 16-5288.

By: s/ Melissa A. Chuderewicz Melissa A. Chuderewicz PEPPER HAMILTON, LLP Attorney for Plaintiff Otsuka Pharmaceutical Co., Ltd. Dated: September 2, 2016



EXHIBIT A

"TIDE7VilTh UTEq1111017111V199111111111111 PIII

1111016 11111111N Il1111111111111111611111911111111MHIMMIIIIMINEEIMIUM

1111111111 111111111 IIIIIH 11116116 1111111111 16161111 I1111I1111l1l11 varillihT05)11 LL.—^1111011/MENZIEIREMMOHnittVellaigiplaiMINPOO

r--- Case 1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16 Page 2 of 89 PagelD: 14I•

i......-. -----p---•••••.:•F...,, .0-, uri,,

I 2'..----:1-r•611 .......-0-v..-•,r _Iit 11 t 14 t! e r

7, 1 ig allikil P-'014,794.4%*,

1 u 7597160N

'-'-i". •Iiii. -----isusam

T9).&1014'"X10)1Wilt011it Pl3ES,

UNITED STATES DEPARTMENT OF COMMERCE

United States Patent and Trademark Office

August 11, 2016

THIS IS TO CERTIFY THAT ANNEXED HERETO IS A TRUE COPY FROM

THE RECORDS OF THIS OFFICE OF:

U.S. PATENT: 9,359,302

ISSUE DATE: June 07, 2016

By Authority of the

Under Secretary of Commerce ford ntellectual Propertyand Director of the United Statet at, and Trademark Office

i4e. itiLVI HOLLEY

Certify 'le Officer

v V V

s'•.

61110111 ^^^111111-MIIIIIIMIRII6I111111111111, (WM

it,, I.,

Case 1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16 Page 3 of 89 PagelD: 15

MERIN 111111111101110111111010 IIUS009359302B2

(12) United States Patent (10) Patent No.: US 9,359,302 B2Bando et al. (45) Date of Patent: *Jun. 7, 2016

(54) LOW HYGROSCOPIC ARIPIPRAZOLE DRUG (52) U.S. Cl.SUBSTANCE AND PROCESSES FOR THE CPC CO7D 215/227 (2013.01); CO7D 215/22

PREPARATION THEREOF (2013.01); C07B 2200/13 (2013.01); YIOT428/2982 (2015.01)

(71) Applicant: OTSUKA PHARMACEUTICAL CO., (58) Field of Classification SearchLTD., Tokyo (JP) CPC CO7D 401/12; CO7D 215/22

USPC 544/363; 514/253.07(72) Inventors: Takuji Bando, Tokushima (JP); Satoshi

See application file for complete search history.Aoki, Tokushima (JP); Junichi

Kawasaki, Tokushima (JP); Makoto

Ishigami, Tokushima (JP); Youichi (56) References CitedTaniguchi, Tokushima (JP); TsuyoshiYabuuchi, Tokushima (JP); Kiyoshi U.S. PATENT DOCUMENTS

Fujimoto, Tokushima (JP); Yoshihiro4,438,119 A 3/1984 Allen et al.

Nishioka, Tokushima (JP); Noriyuki 4,687,772 A 8/1987 Alderdice et al.Kobayashi, Tokushima (JP); Tsutomu 4,734,416 A 3/1988 Banno et al.

Fujimura, Tokushima (JP); Masanori 4,771,053 A 9/1988 Cott et al.4,983,607 A 1/1991 Manoury et al.

Takahashi, Tokushima (JP); Kaoru Abe, 5,006,528 A 4/1991 Oshiro et al.Tokushima (JP); Tomonori Nakagawa, 5,073,377 A 12/1991 Alexander et al.Tokushima (JP); Koichi Shinhama, 5, 162,375 A 11/1992 Nicholson et al.

Tokushima (JP); Naoto Utsumi, 5,200,410 A 4/1993 Traber et al.5, 385,914 A 1/1995 Fujioka et al.

Tokushima (JP); Michiaki Tominaga, 5,504,093 A 4/1996 Gelfand et al.Tokushima (JP); Yoshihiro Ooi, 5,652,247 A 7/1997 Ogawa et al.Tokushima (JP); Shohei Yamada, 5, 691,330 A 11/1997 Nakao et al.

5,824,680 A 10/1998 Turner et al.Tokushima (JP); Kenji Tomikawa, 6,267,942 B1 7/2001 Mori et al.Tokushima (JP) 6,267,989 B1 7/2001 Liversidge et al.

7,053,092 B2 5/2006 Jordon et al.

(73) Assignee: Otsuka Pharmaceutical Co., Ltd., 8,017,615 B2* 9/2011 Bando et al. 514/253.07

Tokyo (JP) 8,399,469 B2 3/2013 Bando et al.8,580,796 B2 11/2013 Bando et al. 514/253.07

Notice: Subject to any disclaimer, the term ofthis (Continued)patent is extended or adjusted under 35

FOREIGN PATENT DOCUMENTSU.S.C. 154(b) by 93 days.This patent is subject to a terminal dis- AU 2002226752 13 8/2002

CA 1117110 Al 1/1982claimer.(Continued)

(21) Appl. No.: 14/049,777OTHER PUBLICATIONS

(22) Filed: Oct. 9, 2013Baptista et al., "Long Term Administration of Some Antipsychotic

(65) Prior Publication Data Drugs Increases BodyWeight and Feeding in Rats. Are D2 DopamineReceptors Involved?" Pharmacology Biochemistry & Behavior, vol.

US 2014/0309236 Al Oct. 16, 2014 27, No. 3, pp. 399-405 (1987).(Continued)

Related U.S. Application Data

(63) Continuation of application No. 13/350, 117, filed on Primary Examiner James 0 WilsonJan. 13, 2012, now Pat. No. 8,580,796, which is a Assistant Examiner Ebenezer 0 Sackeycontinuation of application No. 10/333,244, filed as (74) Attorney, Agent, or Firm —Finnegan, Henderson,application No. PCT/JP02/09858 on Sep. 25, 2002, Farabow, Garrett & Dunner LLPnow abandoned.

(30) Foreign Application Priority Data (57) ABSTRACT

Sep. 25, 2001 (JP) 2001-290645 The present invention provides low hygroscopic forms ofNov. 14, 2001 (JP) 2001-348276 aripiprazole and processes for the preparation thereofwhichMar. 27, 2002 (CA) 2379005 will not convert to a hydrate or lose their original solubility

even when a medicinal preparation containing the anhydrous(51) Int. Cl. aripiprazole crystals is stored for an extended period.

CO7D 401/12 (2006.01)C07D 215/22 (2006.01)CO7D 215/227 (2006.01) 310 Claims, 31 Drawing Sheets

Copy provided by USPTO from the PIRS Image Database on 08/10/2016

Copy provided by USPTO from the PIRS 08/10/2016


US 9,359,302 B2Page 2

(56) References Cited European Patent Office, conununication dated Mar. 10, 2014, for-

warding letter of opponent Chemo Iberica, S.A. dated Mar. 5, 2014,U.S. PATENT DOCUMENTS regarding EP1712225.

European Patent Office, communication dated Mar. 20, 2014, for-8,642,760 B2 2/2014 Bando et al. 544/363 warding Decision of the Technical Board of Appeal dated Jul. 5,8,993,761 B2 3/2015 Bando et al. 2013, regarding EP1330249.

2002/0076437 Al 6/2002 Kothari et al. European Patent Office, communication dated Mar. 27, 2014, for-2002/0156067 Al 10/2002 Wong et al.

warding letter of opponentActavis Group PTC dated Mar. 20, 2014,2003/0027817 Al 2/2003 Tollefson2010/0069317 Al 3/2010 Forino al regarding EP1712225, including document MAI8, Mutschler et al.,et.2012/0316180 Al 12/2012 Bando et al. "Mutschler Arzneimittelwirkungen: Lehrbuch der

Pharmakologieund Toxikologie, 8th edition, pp. 157-172 (2001).FOREIGN PATENT DOCUMENTS Hirose, "New Schizophrenia Drug Aripiprazole (OPC-14597),

Brain Science (Nou no Kagaku), vol. 20, pp. 1135-1140 (1998).DE 29 12 105 C2 8/1985 Krowczynski et al., "Technologia Postaci Lekow, National Institute

DE 29 12 105 C3 8/1985 of Medical Publications, Warsaw, 1969, pp. 54-63, 78-81, 368-379.

DE 29 53 723 C2 1/1989 Merck Manual 17th ed. Japanese, Nikkei B P, p. 1569-1576, 1999.

EP 0 226 441 6/1987 OfficeAction in Japanese Patent Application No. 2011-133032 datedEP 0 360 077 3/1990 Feb. 28, 2014.EP 0 367 141 5/1990 OfficeAction in JapanesePatent Application No. 2011-133032 datedEP 0 565 274 10/1993 May 14, 2013.EP 0 776 927 B1 6/1997 OfficeAction in JapanesePatent Application No. 2011-133033 datedEP 2 223 702 9/2010 Feb. 28, 2014.GB 2017701 B 10/1979 OfficeAction in JapanesePatentApplication No. 2011-133033 datedJP 54-130587 10/1979JP 55-127371 10/1980 May 14, 2013.

JP 56-46812 4/1981 Office Action in U.S. Appl. No. 13/426,886 dated Apr. 3, 2014.

JP 62-149664 7/1987 Office Action in U.S. Appl. No. 13/749,753 dated May 21, 2014.

JP 2-191256 7/1990 Partial English translation of Merck Manual 17th ed. Japanese,JP A-70135 3/1995 Nikkei BP, p. 1569-1576, 1999.JP 07-364740 11/1995 Partial English translation ofOffice Action in Japanese Patent Appli-JP 9-40648 2/1997 cation No. 2011-133032 dated May 14, 2013.JP 11-508280 10/1997 Partial English translation ofOfficeAction in Japanese Patent Appli-JP 9-301 867 11/1997 cation No. 2011-133033 dated May 14, 2013.JP 9-291034 11/1997 Partial Englishtranslation ofYamada et al., "Effect ofOPC-14597 onJP 11-509865 11/1997 the stimulant-induced dopamine release in rat striatal slices, Japa-JP 11-335286 12/1999

nese Journal ofPsychopharmacology, vol. 16, p. 238 (1996).JP 2001-302499 10/2001WO WO 92/10200 6/1992 Trunko et al., "Aripiprazole in Anorexia Nervosa and Low-WeightWO WO 92/20655 11/1992 Bulimia Nervosa: Case Reports, International Journal of EatingWO WO 93/04681 3/1993 Disorders, vol. 44, No. 3, pp. 269-275, 2011.WO WO 94/09765 5/1994 Yamada et al., "Effect of OPC-14597 on the stimulant-inducedWO WO 94/13620 6/1994 dopamine release in rat striatal slices, Japanese Journal ofWO WO 98/07426 2/1998 Psychopharmacology, vol. 16, p. 238 (1996).WO WO 98/08817 3/1998 "Aripiprazole OPC 14597, Drugs R & 0, 2(1):47-48 (1999).WO WO 99/38864 8/1999 "Aripiprazole, Drugs Fut., 25(9).961-963 (2000).WO WO 99/52870 10/1999 Abe et al., "Effect of 5-{9-[((2,S)-1,4-Benzodioxan-2-WO WO 00/16777 3/2000 ylmethyl)amino]propoxyl -1,3-benzodioxole HCI (MCK-242), aWO WO 01/52855 7/2001 Novel 5-HT1A-Receptor Agonist, on Aggressive Behavior andWO WO 02/060423 A2 8/2002WO WO 02/102297 A2 12/2002 Marble Busying Behavior in Mice;' Jpn. J. Pharmacol., 76:297-304

WO WO 03/026659 Al 4/2003 (1998).WO WO 03/030868 4/2003 Abi-Dargham, "Probing cortical dopamine function in schizophre-

nia: what can DI receptors tell us?" World Psychiatry, 2(3):166-1711 OTHER PUBLICATIONS (2003).1 Abou-Gharbia et al., "Synthesis and Structure-Activity Relationship

English translation of Hirose, "New Schizophrenia Drug ofSubstituted Tetrahydro- and Hexahydro-1,2-benzisothiasol-3-one

Aripiprazole (OPC-14597), Brain Science (Nou no Kagaku), vol. 1, 1-Dioxides and Thiadiazinones: Potential Anxiolytic Agents, J.

20, pp. 1135-1140 (1998). Med. Chem., 35(5):1024-1033 (1989).English translation of Krowczynski et al., "Technologia Postaci Abraham et al., "LSD-Like Panic From Risperidone in Post-LSD

Visual Disorder, Journal of Clinical Psychopharmazology,Lekow, National Institute of Medical Publications, Warsaw, 1969,16(3):238-241 (1996).pp. 54-63, 78-81, 368-379.Aceto et al., "Suppression of Opiate Withdrawl and Cocaine

English translation of Office Action in Japanese PatentApplication..Hyperarousal Syndromes by Buspuone, Arzneun.-Forsch./DrugNo. 2011-133032 dated Feb. 28, 2014.Res., 41(11), Nr. 9, pp. 942-945 (1993).

I English translation of Office Action in Japanese Patent ApplicationNo. 2011-133033 dated Feb. 28, 2014.

Addington et al., "Cognitive functioning and positive and negativesymptoms in schizophrenia, Schizophrenia Research 5:123-134

European Patent Office submission of Otsulca Pharmaceutical Co., (1991).Ltd. during appeal T 801/10-3.3.01 for EP1621198 dated Jan. 16, Affidavit ofBruce Sugriv Singh swonr Jan. 19, 2012 in case No. NSD2014. 121/2012 concerninc Australian Patent Nos. 2002226752 andEuropean Patent Office submission of Otsuka Pharmaceutical Co., 2005201772 (including Exhibits BSS-3 to BSS-15).Ltd., regarding appeal T 2059/13-3.3.02 for EP1712225 dated Nov. Affidavit ofChristopher John Easton affirmed May 26, 2010, in case

26, 2013. No. NSD 1116/2009 concerning Australian Patent No. 2002334413.1. European Patent Office, communication dated Jan. 28, 2014, for- Affidavit of Professor CliveAllan Prestidge affirmed Oct. 12, 2009,

warding letter ofopponent Sanovel Ilac Sanayi Ve Ticaret a.S, dated in case No. NSD 1116/2009 concerning Australian Patent No.Jan. 21, 2014, regarding EP1712225, including annexes WuW1 and 2002334413.WuW2. Affidavit of Professor Cools (2008), pp. 1-5.

Image Database on


US 9,359,302 B2Page 3

(56) References Cited Au1ton, Pharmaceutics: The Science of Dosage Fonn Design,Churchill Livingstone, Edinburgh, 1988, pp. 8-9 and 223-226.

OTHER PUBLICATIONS Australian Government, IP Australia Examiner's first report on

patent application No. 2002334413, dated Aug. 13, 2003.Affidavit of Professor Patrick Dennistoun McGony dated Feb. 21, Ausnalian Government, IP Australia Examiner's report No. 2 on

2012, in case No. NSD 121/2012 concerning Australian Patent Nos. patent application No. 2002334413, dated Mar. 5, 2004.2002226752 and 2005201772 (including Exhibits PDM-5 to 7, Australian Government, IP Australia Ex er's report No. 3 onPDM-9 to PDM-14). patent application No. 2002334413, dated Aug. 27, 2004.Agmo et al., "Dopamine and Sexual Behavior in the Male Rabbit, Australian Patent Office, Search Report and Written Opinion rePharmacol. Biochem. Behav., 55:289-295 (1996). Application No. 200302928-7, dated Sep. 30, 2004.Agnew et al., "Dorlands illustratedmedical dictionary, 24th Edition, Australian Therapeutic Goods AdmMistration, Australian Public1965, W:B: Saunders Company, Philadelphia, p. 1088.

Assessment Report for Aripiprazole, dated Apr. 2011.Aguirre, Introduction a la Tecnologia Famiaceutica, vol. 1, pp. 92,96, and 117 (1989).

Banov et al., "Clozapine Therapy in Refractory Affective Disorders:

Ahlenius et al., "Effects of Selective Dopamine DI and D2 Antago- Polarity Predicts Response to Long-Term Follow-Up, J. Clin. Psy-nists on Male Rat Sexual Behavior, Experientia, 46:1026-1028 chiatry, 55(7):295-300 (1944) (Abstract).(1990). Bartoszyk, "Anxiolytic Effects of Dopamine Receptor Ligands: I.

Ahlenius et al., "Specific Involvement of Central 5-HT IA Receptors Involvement of Dopamine Autoreceptors, Life Sciences, 62:649-

in the Mediation ofMale Rat Ejaculatory Behavior, Neurochemical 663 (1998).Research, 22(8):1065-1070 (1997). Bauer et al., "Pharmazeutische Technologic, Georg Thieme Verlag,Ajit, "Does Aripiprazole Have a Role in Treating Cognitive Impair- Stuttgart, pp. 75 81 (1986).ment in Parkinson's Disease, J. Neuropsychiatry Clin. Neurosci., Bazire, "Psychotropic Drug Directory 2001/02: The professionals'19(2):205-506 (2007). pocket handbook and aide memoire, pp. 78-83 (2001).Alfieri et al., "Comparative efficacy of a single oral dose of Beers, M.D. et al., "The Merck Manual of Diagnosis and Therapy,ondansetron and of busipirone against cisplatin-induced emesis in seventeenth edition" Merck Research Laboratories, Whitehouse Sta-cancer patients, British Journal of Cancer, 72:1013-1015 (1995). tions, N.J., pp. 1513-1516, (1999).Amended Statement of Grounds of Opposition filed Mar. 17, 2011, Benabarre et al., "Bipolar disorder, schizoaffective disorder andfor Australian Patent No. 2007201701 byAlphaphann Pty. Ltd. schizophrenia: epidemiologic, clinical and prognostic differenCes,American Psychiatric Association, "DSM-IV Classification for Eur. Psychiatry 16(3):167-172 (2001) (Abstract).Bipolar Disporders, Quick Reference to the Diagnostic Criteria.

Bjorvatn et al., "Sleep/walkingeffects ofa selective 5-HT1Areceptorfrom DSM-IV, pp. 24-25 (1994). agonist given systemically as well as perfused iin the dorsal rapheAmerican Psychiatric Association, "DSM-IV-TR, Diagnostic andnucleus in rats, Brain Research, 770:81-88 (1997).Statistical Manual of Mental Disorders, Fourth Edition, "Mood dis-

orders", 345-428 (2000).Boast et al., "5HT Antagonists Attenuate MK801-Impaired Radial

American Psychiatric Association, "DSM-IV-TR, Diagnostic and Ann Maze Performance in Rats, Neurobiology of Learning and

Statistical Manual of Mental Disorders, Fourth Edition, "Pervasive Memory 71, pp. 259-271 (1999).Developmental Disorders, 69-75 (2000). Bochner et al., Therapeutic Guidelines: Psychotropic (version 4),Angst et al., "Prevalence ofBipolar Disorders: Traditional and Novel 2000, pp. 1, 2, 4, and 115-122.

Approaches, Clin. Appr. Bipol. Disord. 1:10-14 (2002). Bowden, "Novel Treatments for Bipolar Disorder, Exp. Opin.Aoki et al., "Study on Crystal Transformation of Aripiprazol"; 4th Invest. Drugs, 10(4):661-671 (2001).Japanese-Korean Symposium on Separation Technology, pp. 937- Bristol Myers Squibb & Otsuka, Package insert for Abilify® tablets,940, (1996). Sep. 2011.Aoki et al., Poster accompanying "Study on Crystal Transformation Bristol-Meyers Squibb Press Release, "New Data Presented Today atofAripiprazol, Fourth Japanese-Korean Symposium on Separation American Psychiatric Association Annual Meeting, May 22, 2002.Technology (1996). Brittain, "Polymorphism in Pharmaceutical Solids, Drugs and theAouizerate et al., "Updated Overview of the Putative Role of the Pharmaceutical Science, vol. 95, Chapter entitled: "Methods for theSerotoninergic System in Obsessive-compulsive Disorder, Characterization of Polymorphs—X-Ray Powder Diffraction, pp.Neuropsychiatric Disease and Treatment, 1(3):231-243 (2005). 235-238, 1999.Appeal by Egish Died'Jserdiar Nail'Jvanoshan Mukede Brittain, "Polymorphism in Pharmaceutical Solids, NewYork, pp.Resven'Jtarshashag from the decision oftheArbitrazh Court ofMos-

cow, in re Case No. A40-115364/12-12-530, issued Dec. 4, 2012.334-335 (1999).Brittain, "Spectral Methods for the Characterization of PolymorphsApr. 10, 2008, Communication from the European Patent Officeand Solvates, Journal of Pharmaceutical Sciences, 86(4):405-412forwarding Notices ofOpposition submitted byTeva Pharmaceutical

Ind., Ltd. And Stada Arzneimittel AG. (1997).Apr. 12, 2010, Communication from European Patent Office, for- Brittain, Polymorphism in Pharmaceutical Solids, Marcel Dekker,warding a letter from opponent 01, Teva Pharmaceutical Industries Inc., NewYork, 1999, pp. 235-237 and 270-271.

Limited, dated Mar. 29, 2010, regarding the Appeal ofEP Patent No. Brown et al., "Switching Outpatients With Bipolar or Schioaffective1330249. Disorders and Substance AbuseFrom Their Current Antipsychotic to

Apr. 12, 2010, Communication from European Patent Office, for- Aripiprazole, J. Clin. Psychiatry, vol. 66, No. 6, pp. 756-760 (2005).warding a letter from opponent 03, Pharmaceutical Works Buckley et al., "When Symptoms Persist: Clozapine AugmentationPolpharma, dated Mar. 22, 2010, regarding the Appeal of EP Patent Strategies, Schizophrenia Bulletin, 27(4):615-628 (2001).No. 1330249, including Documents D15a (Experimental Burris et al., "Aripiprazole is a high affinity partial agonist at human

Results(D15) Obtained in 2006), D15b (Further data from experi- D2 dopamine receptors, Int. J. Neuropsychopharmacol, 3 (Supplmental results as obtained by Opponent 03 in 2006), and D15c 1):S129 (2000).(Experimental results (D15c)—a Second Series ofexperiments). Caira, "Crystalline PolymorphismofOrganic Compounds, pp. 165-

Apter et al., "Buspirone: Future Directions, Journal of Clinical 166, (1988).Psychophannacology, 19(1):86-93 (1999). Canive et al., "Spontaneous Brain Magnetic Activity in SchizphreniaArlde et al., "Ipsapirone Suppresses Food Intake in Food-Deprived Patients Treated With Aripiprazole, Psychopharmacol Bull,Rats by an Action at 5-HT1A Receptors, European Journal ofPhar- 34(1):101-5 (1998).macology, 408:273-276 (2000). Carli et al., "S 15535, a benzodioxopiperazine acting as presynapticAug. 9, 2012, Communication from European Patent Office, for- agonist and postsynaptic 5-1IT1A receptor antagonist, prevents the

warding a letter from opponent 02, Stall Arzneimittel AG, dated impairment of spatial learning caused by intrahippocampalAug. 6, 2012, regarding the appeal of EP Patent No. 1621198. scopolamine, British J. Pharmacology, 128:1207-1214 (1999).


Copy provided by USPTO from


US 9,359,302 B2Page 4

(56) References Cited Ebenezer et aL, "Effects of the 5-HT1A Receptor Agonist 8-0H-DPAT on Operant Food Intake in Food-DeprivedPigs, Physiology&

OTHER PUBLICATIONS Behavior, 67(2):213-217 (1999).Ebsworth, et al., "Diffraction by powders, Structural Methods in

Carli et al., "Stimulation of 5-HT1A receptors in the dorsal raphe haorganic Chemistry, Blackwell Scientific Publications, 2nd ed., p.reverses the impairment of spatial learning caused by intrahip- 360 (1991).pocampal scopolamine in rats, European J. Neuroscience. 10:221- Ecuadorian Institute of Intellectual Property Patentability Examina-230 (1998). tion Report for Application No. SP06 6521, dated Sep. 5, 2008.Certified English translation ofPlanowski et al., Procesy i paraty w Ecuadorian Institute of Intellectual Property Patentability Examina-technolgii chemiczej, WNT, Warswa (1974) p. 765-771. tion Report for Application No. SP06 6522, dated Sep. 19, 2008.Cervo et al., "Effects of dopaminergic and glutamatergic receptor Ecuadorian Institute ofIntellectual Property, Patentability Examina-antagonists on the establishment and expression ofconditioned loco- tion Report for Application No. SP034434 PCT, dated Jun. 8, 2004.motion to cocaine in rats, Brain Research, 739:31-38 (1996). Elvevaget al., "Cognitive Impainnent in Schizophrenia is the Core of

i Citrome &Volavka, "Atypical antipsychotics: revolutionary or incre- the Disorder, Critical Reviews in Neurobiology, 14(1):1-21 (2000).mental advance?" Expert Rev. Neurotherapeutics, 2(1):69-88 (2002). English abstract of JP 54-130587 published Oct. 9, 1979.

i Clifton et al., "Stimulation and Inhibition of Food Intake by the English abstract of JP 56-46812 published Apr. 28, 1981.i Selective Dopamine D2 Agonist, N-0437: A Meal PatternAnalysis, English translation of a letter from opponent 02, Stada Arzneirnittel

Phannacol. Biochem. Behav, 33:21-26 (1989). AG, dated Aug. 6, 2012, regarding the appeal of EP Patent No.Cohen et al., "Characterization of the Discriminative Stimulus Pro- 1621198.duced by the Dopamine Antagonist Tiapride, J. Phannacol. Exp. English translation of Aripiprazol Experimental Report by Dr.Ther., 283:566-573 (1997). Schmidt, Dec. 23, 2006.Cole et al., "5-HTIA receptor agonists improve the performance of English translation of Aripiprazol Experimental Report by Dr.normal and scopolamine-impairedrats in an operant delayed match- Striegel, Dec. 21, 2006.ing to position task, Psychopharmacology, 116:135-142 (1994). English translation of communication from European Patent OfficeCommunication from European Patent Office dated Jul. 8, 2010, dated Jul. 8, 2010, forwarding Maiwald's statement setting forthforwarding Maiwald's statement setting forth grounds ofappeal for grounds of appeal for European Application Patent No. 05023971.4European Application Patent No. 05023971.4 (EP 1 621 198) dated (EP 1 621 198) dated Jun. 29, 2010.Jun. 29, 2010. English translation of Decision ofthe Arbitrazh Court ofthe City ofComparison of PXRD spectra; Hydrate A and MAD-1541-w---- Moscow in Case No. A40-115364/12-12-530 dated Dec. 4, 2012.matching scales; attached to Opposition submitted by Opponent I English translation of Ecuadorian Institute of Intellectual Property,Teva Pharmaceuticals and transmitted by European Patent Office on Patentability Examination Report for Application No. SP034434Apr. 27, 2009, in EP Patent No. 1 330 249. PCT, dated Jun. 8, 2004.Comparison ofPXRD spectra; Hydrate A and MAB-1541-w—spec- English translation of European Patent Office Submission oftra aligned to tak account of systematic error attached to Opposition Ratiophann GmbH in Opposition to European Patent No. 1330249,submitted by Opponent I Teva Pharmaceuticals and transmitted by transmitted Jul. 2, 2010.European Patent Office on Apr. 27, 2009, in EP PatentNo. 1330 249. English translation of European Patent Office Submissiotn ofConley et al., "Olanzapine compared with chlorpromazine in treat- Ratiopharm GmbH in Opposition to European Patent No. 1330249,ment-resistant schizophrenia, American Journal of Psychiatry, transmitted Jul. 21, 2010, submitting Projektbericht Aripiprazol by155(7):914-920 (1998). Roland Boese and Carsten Schauerte (Document D37 referenced inConley et al., "Treatment-resistant schizophrenic patients respond to the European Patent Office Submission of Ratiopharm GmbH inclozapine after olanzapine non-response, Biol. Psychiatry, 46:73-77 Opposition to European Patent No. 1330249, transmitted Jul. 2,(1999). 2010).Connor et al., "The Use of Aripiprazole in Obsessive-Compulsive English translation of European Patent Office, Communication of a

Disorder: Preliminary Observations in 8 Patients, J. Clin. Psycbia- notice ofopposition for EP Application No. 06015782.3/ EP Patenttry, 66(1):49-51 (2005). No. 1712225, dated Jan. 26, 2012, forwarding Helm AG's Jan. 6,Correll, "Assessing and Maximizing the Safety and Tolerability of 2012, submission/Antipsychotics Used in the Treatment ofChildren and Adolescents, English translation of Examination Report Aripiprazole by RolandJ. Clin. Psychiatry, 69(Supp 4):26-36 (2008). Boese, dated May 31, 2010 (Document D36 referenced in the Euro-Cottraux et al., "A Controlled Study of Cognitive Behavior Therapy

pean Patent No. 1330249, transmitted Jul. 2, 2010).with Buspirone or Placebo in Panic Disorder with Agoraphobia,British Journal ofPsychiatry 167:635-641 (1995). English translation ofexcerpt from ExaminationGuideline forPatent

Craig & Young, "1-Benzylpiperazine, Organic Syntheses, 42:19 and Utility Model in Japan, Part VII: Examination Guideline for

(1962). Inventions in Specific Fields, Ch. 3 Medicinal Inventions, p. 5,Cuesta et al., "Effects of Olanzapine and Other Antipsychotics on attaches to the Notice of Information Disclosure by Third PartyCognitive Function in Chronic Schizophrenia: A longitudinal Study, issued by the Japanese Patent Office in Japanese Patent ApplicationSchizophrenia Research, 48:17-28 (2001). No. 2007-179275 on May 31, 2010.

Daniel et al., "Aripiprazole, a novel antipsychotic: Overview of a English translation ofLaboratory Report by Ratiopharm, dated Sep.phase II study result, Int. J. Neuropsychophannacol, 3 (Suppl 22, 2008 (Document D38 referenced in the European Patent Office

1):S157 (2000). Submission of Ratiopharm GmbH in Opposition to European PatentDavis et al., "Ziprasidone, CNS Drugs 8(2):153-159 (1997). No. 1330249, transmitted Jul. 2, 2010).Decision of the Arbitrazh Court of the City of Moscow in Case No. English translation of Notice of Information Disclosure by ThirdA40-115364/12-12-530 dated Dec. 4, 2012. Party issued bythe Japanese Patent Office in Japanese Patent Appli-Declaration of Markus Antonietti executed Jan. 29, 2013, during cation No. 2007-179275 on May 31, 2010.

opposition proceedings for European Patent No. 1330249, including English translation ofNovelty Search Report from HungarianAppl i-Exhibits A and B. cation No. P0600141, dated Feb. 19, 2008.Declaration ofNikkiso Co., Ltd. byYasuo Kizawa dated Feb. 7, 2013, English translation ofOfficeAction in Taiwanese Patent Applicationduring opposition proceedings for European Patent No. 1330249, No. 098116881 dated May 17, 2010.

including "Pamphlet of Microtrac HRA" and "Pamphlet ofNanotrac English translation ofpetition ofSanovel Ilac Sanayi ye Ticaret A.S.UPA". regarding Turkish patent TR 2006 02467 T4, submitted to the

Dziegilewski, "Selected Mood Disorders, DSM-IV-TR in Action, Istanbul 3rd Civil Court ofIntellectual and Industrial Property Rights2nd Edition, pp. 297-298 (2010). on Jun. 6, 2013.

the PIKS Image Uatabase on 08/10/2016


US 9,359,302 B2Page 5

(56) References Cited European Patent Office submission ofOtsuka Pharmaceutical Co.,Ltd. in European Patent Application No. 02782507.4-2101, dated

OTHER PUBLICATIONS Dec. 15, 2004.

European Patent Office submission ofOtsuka Pharmaceutical Co.,English translation ofRequest for declaratory judgement on lack of Ltd. in European Patent Application No. 04002427.5, dated Sep. 8,infringement by Generica Ilac Sanayi ve Tic A.S. dated Mar. 27, 2008, including Annexes 1-3.2013, before the Istanbul Court on Duty for Intellectual and Industrial European Patent Office submission ofOtsuka Pharmaceutical 'Cb.,Rights. Ltd. in European Patent Application No. 06015782.3, dated Aug. 19;English translation of Russian Patent Office Submission of Egis 2010.GyOgyszergyar NYRT in Opposition to Russian Patent No. 2259366 European Patent Office submission ofOtsuka Pharmaceutical Co.,(Application No. 2003101334), including Enclosure 1, transmitted Ltd. in European Patent Application No. 06015782.3, dated Nov. 13,Oct. 5, 2011. 2008, including Comparative Experiments.English translation ofTechnical Opinion 1907 from the Colombian European Patent Office submission ofOtsuka Pharmaceutical Co.,Superintendence of Industry and Trade, dated Jul. 3, 2009. Ltd. in European Patent Application No. 08000357.7-2101, datedEnglish translation ofTechnical Opinion 2309 from the Colombian Mar. 5, 2009, including Annexes 1-3.Superintendence of Industry and Trade, dated Dec. 28, 2007. European Patent Office submission ofOtsuka Pharmaceutical Co.,English translation of the Office Action from Japanese Patent Office Ltd. in European Patent Application No. 08000358.5, dated Apr. 27,issued in Japanese Patent Application No. 2007-179275 on Apr. 13, 2009, including Annexes 1-3.2011. European Patent Office submission of Otsuka Pharmaceutical Co.,English translation of the Office Action from Japanese Patent Office Ltd. in European Patent Application No. 08000359.3-2101, datedissued in Japanese Patent Application No. 2007-179275 on Oct. 22, Mar. 5, 2009, including Annexes 1-3.2010. European Patent Office Submission of Otsuka Pharmaceutical Co.,European Medicines Agency report on aripiprazole, 2005. Ltd. in European Patent Application No. 08000360.1-2101, datedEuropean Patent Office Communication ofa notice ofopposition for Mar. 5, 2009, inclusing Annexes 1-3.EPApplication No. 04002427.5-2101/ EP Patent No. 1419776, dated European Patent Office submission of Otsuka Pharmaceutical Co.,Jan. 19, 2011, forwardingTeva Pllarmaceutical Industries Ltd.'s Jan. Ltd. in the appeal of European Patent No. 1621198, dated May 27,13, 2011, submission including Experimental Report 1 and Annexes 2011, including Affidavir of Bryan L. Roth, M.D., Ph.D., executed1-3. May 23, 2011.

European Patent Office Decision revoking European Patent No. EP- European Patent Office Submission of Pentafarma S.A. in Opposi-B-1330249 and Provision ofthe minutes ofthe oral proceedings, Jul. tion to European Patent No. 1712225, dated Apr. 11, 2013, including7, 2009. D55 (excerpt from online Dictionary).European Patent Office Decision revoking European Patent No. EP- European Patent Office Submission of Ratiopharm GmbH in Oppo-B-1419776 and Provision ofthe minutes ofthe oral proceedings, Jun. sition to European Patent No. 1330249, transmitted Jul. 2, 2010.

5, 2012. European Patent Office Submission ofRatiopharm GmbH in Oppo-European Patent Office Submission ofEgis GyOgyszergyár NYRT in sition to European Patent No. 1330249, transmitted Jul. 21, 2010,Opposition to European Patent No. 1330249B1, transmitted Apr. 27, submitting Projektbericht Aripiprazol by Roland Boese and Carsten2009. Schauerte (Docmnent D37 referenced in the European Patent Office

European Patent Office submission of Otsuka Pharmaceutical Co.., Submission ofRatiopharmGmbH in Opposition to European PatentLtd. during appeal for European Patent No. 1419776, dated Oct. 15, No. 1330249, transmitted Jul. 2, 2010).2012, including enclosures D23, D24, and D25. European Patent Office Submission of Teva Pharmaceutical Ind.,European Patent Office submission of Otsuka Pharmaceutical Co., Ltd., submitting facts andarguments in theappeal ofEuropeanPatentLtd. during opposition proceedings for European Patent No. Applciation No. 05023971.4 (EP 1 621 198), dated Jun. 29, 2010.

1712225, dated No. 5, 2012, including enclosure Table listing all European Patent Office Submission ofTeva Pharmaceutical Indus-cited documents, D41, D42, and D51. tries Limited in Opposition to European Patent No. 1330249, dated

European Patent Office submission of Otsuka Pharmaceutical Co., Apr. 18, 2008.Ltd. during opposition proceedings for European Patent No. European Patent Office submission of Teva Pharmaceutical Indus-1330249, dated Mar. 6, 2009, including x-ray and DSC spectra for tries Ltd. in opposition to European Patent No. 1419776, dated Apr.Samples 1 and 2 and p. 939 ofD2. 16, 2012.European Patent Office submission of Otsuka Pharmaceutical Co., European Patent Office Submission ofTeva Pharmaceutical Indus-Ltd. during opposition proceedings for European Patent No. tries Ltd. in Opposition to European Patent No. 1712225, dated Apr.1330249, dated Mar. 7, 2013. 12, 2013.

European Patent Office submission of Otsuka Pharmaceutical Co., European Patent Office, communication dated Dec. 13, 2005, ofLtd. during opposition proceedings for European Patent No. observationsofa thirdpartyregarding EPApplicationNo. 02782507.

1330249, dated Oct. 25, 2012, including enclosures D39 and D40. 4/EP Patent No. 1330249, forwarding letter dated Nov. 30, 2005.

European Patent Office submission of Otsuka Pharmaceutical Co., European Patent Office, communication dated Jan. 27, 2006, ofLtd. during opposition proceedings for European Patent No. observations ofa thirdpartyregardingEPApplication No. 02782507.

1419776, dated Apr. 3, 2012, including Declarations 1 and 2 ofMr. 4/EP Patent No. 1330249, forwarding letter dated Jan. 17, 2006 and

Aoki, executed Apr. 2, 2012. documents DI to D7.

European Patent Office submission of Otsuka Pharmaceutical Co., European Patent Office, communication dated Jul 16, 2013, regard-Ltd. during opposition proceedings for European Patent No. ing minutes of oral proceedings held Jul. 5, 2013, in Appeal No.

1419776, dated Aug. 29, 2011, including DSC and XRD data for T1772/09-3.3.01 regarding EP 1330249.

Type-2 Crystal. European Patent Office, communication dated Jun. 7, 2013, regard-European Patent Office submission ofOtsuska Pharmaceutical Co., ing oppostition to EP Application No 02782507.4/EP Patent No.Ltd. during opopsition proceedings for European Patent No. 1330249, forwarding submission of Egis Gyógyszergyar NYRT

1419776, dated Feb. 24, 2012, including Annex 1, overview of the dated Jun. 4, 2013, including documents D43 (printout of http://powder C-ray diffraction spectra ofType-1, Type-2 and Type-C(Part showadenko.us/product/thermal.php "Thermal Functional Filler1-Part 4) and Annex 2, overview of the powder C-ray diffraction Alumina hBN"), and D45b (printout pf http://www.osrok.com/spectra ofType-2 crystals, Sample MT-2178 (Part 1) and PZ-8057-3 products/catalog/psa/LA-910.pdf "Horiba LA-910, Laster Scatter-

(Part 2) and Type-C crystals. ing Particle Size Distribution Analyzer").European Patent OFfice submission of Otsuka Pharmaceutical Co., European Patent Office, communicaiton dated May 10, 2013, for-Ltd- during the appeal of European Patent No. 1330249, dated Nov. warding letter ofopponent Teva Pharmaceutical Industries Ltd dated

17, 2009, including Experimental Report with Annexes 1-3. May 6, 2013, inAppeal No. T1555/12-3.3.02 regarding EP1419776.

Copy provided by USPTO from the PIRS Image Database on


US 9,359,302 B2Page 6

(56) References Cited February 12, 2004, Communication from European Patent Office,forwarding thirdparty observations regarding EP Patent Application

OTHER PUBLICATIONS No. 02782507.4, dated Jan. 30, 2004.Federal Court of Australia, Judgement of J. Yates, dated Mar. 16,

European Patent Office, communication dated May 25, 2005, of 2012, in case No. NSD 121/2012 concerning Australian Patent Nos.observations ofa thirdparty regarding EP Application No 02782507. 2002226752 and 200501772.4/EP Patent No. 1330249, forwarding letter ofMaprimed S.A. dated Federal Court of Australia, Transcript of Proceedings in case No.May 17, 2005. NSD 121/2012, dated Feb. 3, 2012, concerning Australian PatentEuropean Patent Office, Communication ofanotice ofopposition for Nos. 2002226752 and 2005201772.EP Application No. 06015782.3/ EP Patent No. 1712225, dated Jan.

Fedoroff, "Bu off'one Hydrochloride in the Treatment ofan Atypical26, 2012, forwarding Actavis Group PTC EHF's Jan. 5, 2012, sub-mission....Paraphilia, Archives ofSexual Behavior, 21(4):401-406 (1992).

Ferrari et al., "The selective D2 Doparnine Receptor AntagonistEuropean Patent Office, Communication ofa notice ofopposition forEP Application No, 06015782.3/ EP Patent No. 1712225, dated Jan. Eticlopride Counteracts the Ejaculatio Praecox Induced by the Selec-

26, 2012, forwarding Chemo Iberica, S.A.' s Jan. 6, 2012, submis- tive D2 Dopamine Agonist SND 919 in the Rat, Life Sciences,sion. 55(14):1155-1162 (1994).European Patent Office, Communication ofa notice ofopposition for Findling et al., "An open clinical trial ofrisperidone monotherapy inEP Application No. 06015782.3/ EP Patent No. 1712225, dated Jam young children with autistic disorder, Psychopharmacol. Bull.,26, 2012, forwarding Helm AG's Jan. 6, 2012, submission. 33(1):155-159 (1997) (Abstract).European Patent Office, Communication ofanotice ofopposition for Findling et al., "Aripiprazole in Children with Attention-Deficit/EP Application No. 06015782.3/ EP Patent No. 1712225, dated Jan. Hyperactivity Disorder, J. Child and Adolescent Psychophannc.,26, 2012, forwarding Hexal AG's Jan. 4, 2012, submission. 18(4):347-354 (2008).European Patent Office, Communication ofa notice ofopposition for Fleischhacker et al., "A double-blind, randomizedcomparatice studyEP Application No. 06015782.3/ EP Patent No. 1712225, dated Jan. ofaripiprazole and olanzapine in patients with schizophrenia, Biol.26, 2012, forwarding Pentafarma S.A.'s Jan. 5, 2012, submission. Psychiatry, 65:510-517 (2009).European Patent Office, Communication ofa notice ofopposition for Forbes et al., "(R)-3, N-Dimethyl-N41-Methy1-3-(4-Methyl-EP Application No. 06015782.3/ EP Patent No. 1712225, dated Jan. Piperidin-1 -y1)Propyl]Benzenesulfonamide: The First Selective26, 2012, forwarding Sanovel Ilac Sanayi ve Ticaret AS.'s Jan. 3, 5-HT7 Receptor Antagonise% Journal of Medical Chemistry,2012, submission. 41(5):655-657 (1998).European Patent Office, Comnmnication ofa notice ofopposition for Ford et al., "Pharmaceutical Thermal Analysis: Techniques andEP Application No. 06015782.3/ EP Patent No. 1712225, dated Jan. Applications, pp. 210-212 (1989).26, 2012, forwarding Stada Arzneimittel AG's Jan. 3, 2012, submis- Foreman et al., "Preclinical Studies on LY228729: A Potent andsion. Selective SerotoninIA Agonist, Journal of Pharmacology andEuropean Patent Office, Communication ofa notice ofopposition for Experimental Therapeutics, 267(1):58-71 (1993).EP Application No. 06015782.3/ EP Patent No. 1712225, dated Jan. Fratta et al., "Stress-induced insomnia: opioid-dopamine interac-26, 2012, forwarding Teva Pharmaceutical Industries Ltd.'s Jan. 5, tions, European Journal of Phannacology, 142:437-440 (1987).2012, submission. Friedman et al., "Open-Label Flexible-Dose Pilot Study to EvaluateEuropean Patent Office, International Search Report for Application the Safety and Tolerability ofAripiprazole in Patients with PsychosisNo. PCT/JP02/09858, dated Nov. 14. 2002. Associated with Parkinson's Disease, Movement Disorders,European Patent Office, Summons to attend oral proceedings pursu- 21(12):2078-2081 (2006).ant to Rule 115(1) EPC, EP Patent No. 1330249, Jan. 27, 2009. Frye et al., "Clozapine in bipolar disorder: treatment implications for

European Patent Office, Summons to attend oral proceedings pursu- other atypical antipsychotics, Journal ofAffective Disorders, 48:91-ant to Rule 115(1) EPC, EP Patent No. 1419776, Oct. 25, 2011. 104 (1998).European Patent Office, Summons to attend oral proceedings pursu- Fujii et al, "Sexual Dysfunction in Japanese Patients with Schizo-ant to Rule 115(1) EPC, EP Patent No. 1621198, Oct. 13, 2009. phrenia Treated with Antipsychotics, Prog.European Patent Office, Summons to attend oral proceedings pursu- Neuropsychopharmacol. Biol. Psychiatry, Nov.28, 2009, issue 1878-ant to Rule 115(1) EPC, EP Patent No. 1712225, Feb. 1 2013. 4216.Examination Report Aripiprazole by Roland Boese, dated May 31, Furniss et al., Vogel's Textbook of Practical Organic Chemistry, 5th2010 (Document D36 referenced in the European Patent Office Sub- Ed., pp. 149-151, 1989.mission ofRatiopharm GmbH in Opposition to European Patent No, Further Amended Particulars of Invalidity for Australian Patent No.

1330249, transmitted Jul. 2, 2010. 2002334413, dated Jun. 15, 2011, by Apotex Pty. Ltd.Examiner's Re-examination Report dated Jan. 28, 2009, for Austra- Galeotti et al., "Role of 5-HTIAReceptors in Mouse Passive Avoid-lian Patent No. 2002226752. ance Paradigm, Jpn. J. Pharmacol., 84:418-424 (2000).Examiner's Re-examination Report dated Jan. 28, 2009, for Austra- Garattini et al., "Progress in Assessing the Role of Serotonin in thelian Patent No. 2002334413. Control of Food Intake, Clin. Neuropharmacol., 11(suppl. 1);Examiner's Re-examination Report dated Jan. 28, 2009, for Austra- S8-S32, (1988).Han Patent No. 2005201772. Garcia-Anaya et al., Los Antipsycoticos atipicos: Una Revision,Examiner's Re-examination Report dated Oct. 10, 2006, for Austra- Salud Mental, 24(5):37-43 (2001).lian Patent No. 2002334413. Gelemter et al., "D2 Dopamine Receptor Gene (DRD2) Allele and

Excerpt fromExamination Guidelines for Patent andUtility Model in Haplotype Frequencies in Alcohol Dependent and Control Subjects:Japan, Part VII: Examination Guidelines for Inventions in Specific No Association with Phenotype or Severity of Phenotype,Fields, Ch. 3 Medicinal Inventions, p. 5, attached to the Notice of Neuropsychophannacology, 20:640-649 (1999).Information Disclosure by Third Party issued by the Japanese Patent Gelernter et al., "No Association Between D2 Dopamine ReceptorOffice in Japanese Patent Application No. 2007-179275 on May 31, (DRD2) Alleles or Haplotypes and Cocaine Dependence or Severity2010. ofCocaine Dependence in European-andAfrican-Americans, Biol.Experimental Report (Aripiprazole Hydrate A), D4 from EPO Deci- Psychiatry, 45:340-345 (1999).sion of Jul. 7, 2009, regarding Application No. 02782507.4-2101/ Gentile, "A Systematic Review of Quality of Life and Weight Gain-1330249. related Issues in Patients Treated for Severe and Persistent MentalExperimental Results (D3) provided by Opposition—Pharmaceuti- Disorders: Focus on Aripiprazole, Neuropsychiatric Disease andcal Works Polpharma, transmitted Jan. 16, 2007, by European Patent Treatment, 5:117-125 (2009).Office, Application No. 02782507.4-2101/1330249. Geretsegger et aL, "Ipsapirone in the Treatment ofBulimia Nervosa:Farah, "Atypicality of Atypical Antipsychotics", Prim. Care Com- An Open Pilot Study, International Journal of Eating Disorders,panion, J. Clin. Psychiatry, 7:268-274, 2005. 17(4):359-363 (1995)



US 9,359,302 B2Page 7

(56) References Cited quinolinone (OPC-14597) on Prolactin Release from the Rat Ante-rior Pituitary Gland, J. Pharm, Exp. Ther., 277:137-143 (1996).

OTHER PUBLICATIONS IMellectual Property Office ofSingapore, Search Report and WrittenOpinion for Singaporean Application No. 200302928-7, dated Dec.

Giannini et al., "Behavioral Response to Buspirone in Cocaine and 13, 2004.Phencyclidine Withdrawal" Journal of Substance Abuse Treatment, International Standard, "Particle size analysis-Laser diffraction10:523-527 (1993). methods, ISO 13320-1:1999(E) (1999).Glick et al., "Treatment with atypical antipsychotics: new indications International statistical classification of diseases and related healthand new populations, Journal of Psychiatric Research, 35:187-191

disorders, 10th revision (ICD-10), vol. 1-Systematic directmy, p.(2001). 281, 2010.Goldberg & Gold, "Neurocognitive Deficits in Schizophrenia, in Jan. 10, 2007, Communication from the European Patent OfficeSchizophrenia (Hirsch & Weinberger eds., Blackwell Science Ltd.),1995, pp. 146-162. forwardingaNotice ofOpposition submitted byTeva Pharmaceutical

Goldrnan-Rakic et al., "D1 Receptors in Prefrontal Cells and Cir-Industries Limited.

cuits, Brain Research Reviews, 31:295-301 (2000). Jan. 11, 2007, Communication from the European Patent Office

Goodnick et al, "Aripiprazole: Profile on efficacy and safety, Expert forwarding a Notice of Opposition submitted by Fermion Oy.Opinion on Pharmacotherapy, 3(12):1173-1781(2002). Jan. 15, 2007, Communication from the European Patent OfficeGuille et al., "A Naturalistic Comparison ofClozapine, Risperidone, forwarding a Notice ofOpposition submitted byEgis GyOgyszergyarand Olanzapine in the Treatment ofBipolar Disorder, J. Olin. Psy- Nyrt.chiatry, 61(9):638-642 (2000). Jan. 15, 2007, Communication from the European Patent OfficeHaddjeri et al., "Acute and long-term actions of the antidepressant forwarding a Notice of Opposition submitted by ratiopharm GmbH.drug mirtazapine on central 5-HT neurotransmission, Journal of Jan. 16, 2007, Communication from the European Patent OfficeAffective Disorders 51:255-266 (1998). forwarding a Notice of Opposition submitted by PharmaceuticalHaddjeri et al., "Increased Tonic Activiation of Rat Forebrain Works Polypharma.5-HT1A Receptors by Lithium Addition to Antidepressant Treat- Jan. 31, 2013, Communication from the European Patent Office,ments, Neuropsychopharmacology 22(4):346-356 (2000). forwarding a letter ofopponent Ovi, Pentafarma S.A., dated Jan. 21,Haddjeri et al., "Long-Term Antidepressant Treatments Result in a 2013, regarding opposition proceedings for European Patent No.Tonic Activiation of Forebrain 5-HT1A Receptors, Journal of 1712225.Neuroscience 18(23):10150-10156 (1998). Jordan et al., "InVivo Effects ofAripiprazole on Cortical and StriatalHaensel et al., "Flesinoxan: a prosexual drug for male rats, European.Dopammergic and Serotonergic Function, European Journal ofJournal of Pharmacology, 330:1-9 (1997). Pharmacology, 483: 45-53 (2004).Hammerstad et al., "Buspirone in Parkinson's Disease, Clin.Neurophamiacol., 9(6)556-60 (1986).

Jordan et al., "InVivo Effects ofAripiprazole on Dopaminergic and

Hamon et al., "Alterations ofCentral Serotonin and Dopamine Turn- Serotonergic Function in Rat Prefrontal Cortex and Striatum, Soci-

over in Rats Treated with Ipsapirone and Other ety for Neuroscience Abstracts, Society of Neuroscience, US,5-HydroxytyptaminelA Agonists with Potential Anxiolytic Proper- 2(27):2327, AN87503 (2001).ties, J. Pharmacol. Exp. Ther., 246(2):745-752 (1988). Jordan et al.. "The antipsychotic aripiprazole is a potent, partialHarada et al„ "Aripiprazole Augmentation for a Patient With Partial agonist at the human 5-HTIA receptor, EuropeanRemission ofPanic Disorder, J. Chit. Psychopharmacology, Letters Neuropsychopharmacol., 11(suppl. 3):S268 (2001).to the Editor, 29(3):301-302 (2009). Kane et al., "Aripiprazole for Treatment-Resistant Schizoiphrenia:Harwood et al., "Experimental Organic Chemistry Principles and Results of a Multicenter, Randomized, Double-Blind, ComparisonPractice, Blackwell Scientific Publications), pp. 136-137, (1989). Study Versus Perphenazine, J. Clin. Psychiatry, 68(2):213-223Heinrichs etal., "The Quality ofLife Scale: An Instrument for Rating (2007).the Schizophrenic Deficit Syndrome, Schizophrenia Bulletin, Kane et al., "Clozapine for the treatment-resistant schizophrenic,10(3):388-398 (1984). Arch. Gen. Psychiatry, 45:789-796 (1988).Heinz et al., Organikum, Organish-chemisches Grundpractikum, Kane et al., "Efficacy of Aripiprazole in Psychotic Disorders: Com-VEB Deutscher Verlag der Wissenschaften, Berlin, tables A.32 and parison With Haloperidol and Placebo, Int JA.35 and sections 1.10.2-1.10.4, 1986. Neuropsychopharmacol, 3 (Suppl 1):Abst P01.124 (2000).Hellewell, "Treatment-resistant schizophrenia: Reviewing the Katz et al., "Comparison of risperidone and placebo for psychosisoptions and identifying the way forward, J. Clin, Psychiatry, and behavioural disturbances associated with dementia: A random-

60(Suppl 23):14-19 (1999). ized double-blind trial, Journal of Clinical Psychiatry 60(2):107-Hebnan, Farmacotecnia Teorica y Practice. Tomo IV. Editorial Con- 115 (1999).tinental, S.A., 1981 pp. 1142 and 1165. Kay et al., "The Positive and Negative Syndrome Scale (PANSS) forHirose et al., "Efficacy and favorable side effect profile of Schizophrenia, Schizophrenia Bulletin, 13: 261-276 (1987).aripiprazole determined in rats with apoinorphine-induced stereo- Keck et al., "Anticonvulsants and Antipsychotics in the Treatment of

typy, catalepsy, and ptosis induction, Int. J. Neuropsychopharmacol, Bipolar Disorder, J. Chin. Psychiatry, 59(suppl. 6):74-81 (1998).3 (Suppl 1):S131 (2000). Keck et al., "Antipsychotics in theTreatment ofMood Disorders andHoge et al., "Aripiprazole as Augmentation Treatment of Refractory Risk ofTardive Dyskinesia, J. Clin. Psychiatry, 61(suppl. 4):33-38Generalized Anxiety Disorder and Panic Disorder, CNS Spectr. (2000).13(6):522-527 (2008). Keck et al., "Bipolar Disorder, Advances in the Pathophysiology andHoshino et al., "Blood Serotonin and Free Tryptophan Concentration Treatment of Psychiatric Disorders: Implications for Internal Medi-in Autistic Children, Neuropsychobiology 11: 22-27 (1984). eine, 85(3): 645-661 (2001).Hustig & Norrie, "Managing schizophrenia in the community, MJA Keck, Jr., "TreatmentAdvances in Bipolar Disorder-Making UpforPractice Essentials-Mental Health, 57-62 (1998). Lost Time, Biological Psychiatry, 48(6):430-432 (2000).Inoue et al., "Aripiprazoie, a novel antipsychotic drug, inhibits Keck, Jr., et al., "Bipolar Disorder, Medical Clinics of North

quinpirole-evoked GTPase activity but does not up-regulate America, W.B. Saunders Company, Philadelphia, US, 3(85):645-661dopamine D2 receptor following repeated treatment in the rat (2001).striatum, European Journal of Pharmacology 321:105-111 (1997). Keefe et al., "The Effects of Atypical Antipsychotic Drugs on

Inoue et al., "Differential Effects on D2 Dopamine Receptor and Neurocognitive Impairment in Schizophrenia: A Review and Meta-Prolactin Gene Expression by Haloperidol and Aripiprazole in the analysis, Schizophr Bull, 25:201-222 (1999).Rat Pituitary, Molecular Brain Research, 55: 285-292 (1998). Kern et al., "An Open-label Comparison of the NeurocognitiveInoue et al., "Effects of the Novel Antipsychotic Agent 7444442, Effects of Aripiprazole Versus Olanzapine in Patients With Stable3 -dichloropheny1-1-piperazinyl]butyloxyl -3,4-dihydro-2(1H)- Psychosis, Schizophr Res, 49(1-2); Suppl S:234 (2001).

Copy provided by USPTO from the PIKS image Database on 08/10/2016

Copy provided by USPTO from the MRS Image Database

{Case 1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16 Page 10 of 89 PagelD: 22

US 9,359,302 B2Page 8

(56) References Cited dated Feb. 28, 2012, regarding Opposition to EP Patent No.

1419776B, including a signed version ofExperimental Report DYC3OTHER PUBLICATIONS and Annexes 1 and 2.

Matuszewich et al., "Partial antagonism of8-0H-DPAT'S effects onKern et aL, "The Neurocognitive Effects ofAripiprazole: An Open- male rat sexual behavior with a D2, but not a 5-HT1A, antagonist,Label Comparison with Olanzapine, Psychopharmacology, Brain Research, 820:55-62 (1999).187:312-320 (2006). McCormick, "Treatment with Buspirone in a Patient with Autism,Kikuchi et al "7 {4[-4-(2,3 -Dichloropheny1)-1- Arch. Fam. Med., 6:368-370 (1997).Piperazinyl]Butyloxy}-3,4-Dihydro-2(IH)-Quinolinone (OPC- McDougle et al., "A Double-blind, Placebo-Controlled Study of14597), a New Putative Antipsychotic Drug with Both Presynaptic Risperidone in Adults with Autistic Disorder and Other PervasiveDopamine Autoreceptor Agonistic Activity and Postsynaptic D2 Development Disorders, Arch. Gen. Psychiatry, 55:633-641 (1998).Receptor Antagonistic Activity, J. Pharm. Exp. Ther., 274:329-336 McDougle et aL, "Atypical Antipsychotics in Children and Adoles-(1995). cents with Autistic andOther PervasiveDevelopmental Disorders, J.Kikuchi et al., "Pharmacological profile of OPC-14597, a novel Clin. Psychiatry, 69(Supp 4):15-20 (2008).antipsychotic drug (1): Presynaptic dopamine autoreceptor agonistic McDougle et al., "Lack of efficacy of clozapine monotherapy inactivity and postsynaptic dopamine D2 receptor antagonistic activ- refractory obsessive-compulsive disorder, Am. J. Psychiatry,ity, Japanese Journal ofPharmacology, 67(Suppl. 1):144P(1995). 152(12)1812-1814 (1995).Kohen & Sarcevicr"Central Sleep Apnea in a Geriatric Patient McElroy et al., "Pharmacologic Agents for the Treatment of AcuteTreated with Aripiprazole, Am. J. Ther, 16(2):197-98 (2009). Bipolar Mania, Biol. Psychiatry, 48:539-557 (2000).Kuzmitcheva, "Powder Diffractometry in Materials Technology, Meltzer et al., "Does stimulation of5-HT1A receptors improve cog-part II, pp. 1-2, 75-76, 2006. nition in schizophrenia?" Behavioural Brain Research, vol, 195 pp.Laboratory Report by Ratiopharm, dated Sep. 22, 2008 (Document 98-102 (2008).D38 referenced in the European Patent Office Submission of Meltzer et al., "Multisystems and Circuitry Pharmacotherapy—Ratiopharm GmbH in Opposition to European Patent No. 1330249, Single or Multiple Receptor Targets: Which are Best fortransmitted Jul. 2, 2010). Antipsychotic Drugs, Neuropsychopharmacology 23(52):S73Laitinen, Experimental Report on Aripiprazole Batches, Dec. 18, (2000).2006. Meltzer et al., "Serotonin Receptors: Their Key Role in Drugs toLawler et al., "Interactions ofthe Novel Antipsychotic Aripiprazole Treat Schizophrenia, Progress in Neuro-Psychopharmacology &(OPC-14597) with Dopamine and Serotonin Receptor Subtypes, Biological Psychiatry, 27:1159-1172 (2003).Neuropsychopharrnacology, 20(6). Meltzer, "Evaluating the effects of antipsychotics on cognition inLeo & Del Regno, "Atypical Antipsychotic Use in the Treatment of

Psychosis in Primary Care, Primary Care Companion J. Clin, Psy- schizophrenia, Journal ofChoreal Psychiatry 59(Suppl. 12):35-40chiatry, 2(6):194-204 (2000) (1998).Letter of Third Party dated Apr. 22, 2009, re Response of Mar. 26, Meltzer, "Treatment-resistant schizophrenia—the role of clozapine,2009, to Examiner's Re-examination Report ofAustralianPatent No. Current Medical Reseach and Opinion, I4(2):1-20 (1997).2002334413 dated Jan. 28, 2009. Mendelson et al., "Effects of Buspirone on Sleep and Respiration,Lieberman et al. (eds), Pharmaceutical Dosage Forms (Marcel Dek- Am. Rev. Respir. Dis. 141:1527-1530 (1990).ker Inc, 2nd revised ed.), 1989, pp. 1-130. Micheau et al., "Stimulation of 5-HT1A Receptors by Systemic or

Lieberman, "AtypicalAntipsychotic Drugs as a First-Line Treatment Medial Septum Injection Induces Anxiogenic-like Effectsand Facilof Schizophrenia: A Rationale and Hypothesis, Journal of Clinical tates Acquisition of a Spatial Discrimination Task in Mice, Prog.Psychiatry, 57( Suppl. 1):68-71 (1996). Neuro-Psychopharmacol. & Biol. Psychiat., 23:1113-1133 (1999).Lucki, "Behavioral Studies of Serotonin Receptor Agonists as Anti- Milian et al., "Improving the Treatment of Schizophrenia: Focus on

depressant Drugs, J. Clin. Psychiatry 52(12 Suppl.):24-31 (1991). Serotonin (5-HT)1A Receptors, J. Pharmacol. Exp. Ther.,Lykouras et al., "Obsessive-compulsive symptoms induced by atypi- 295(3):853-61 (2000).cal antipsychotics. A review of reported cases, Progress in Neuro- MIMS Annual 2000, "Antipsychotic agents, pp. 3-258 to 3-281.

Psychopharmacology & Biological Psychiatry, 27:333-346 (2003). Mitsukuni, "Recent Trend of Development of Psychoactive DrugsLykouras et al., "Olanzapine and obsessive-compulsive symptoms, (2)—Antipsychotic Drugs, Jpn. J. Psychopharmacol., 15(3)191-210European Neuropsychophannacology, 10:385-387 (2000). (1995).Malhotra et al., "An Open Clinical Trial of Buspirone in Children Mohs, "Cognition in Schizophrenia: Natural History, Assessment,with Attention-Deficit/Hyperactivity Disorder, J. Am. Acad. Child and Clinical Importance, Neuropsychopharmacology, 21(6):203-Adolesc. Psychiatry, 37(4):364-371 (1998). 210 (1999).Mallikaarjun et al., "The Pharmacokinetics, Tolerability, and Safety Molewijk et al., "Conditioned ultrasonic distress vocalizations inofAripiprazole Following Single and Multiple Oral Dose Adminis- adult male rats as a behavioural paradigm for screening anti-panictration, Int J Neuropsychopharmacol, 3 (Suppl) 1:Abst P01.123 drugs, Psychopharmacology, 117:32-40 (1995).(2000). Monti et al., "Role of Dorsal Raphe Nucleus Serotonin 5-HT1AManfredi et al., "Buspirone: Sedative or Stimulant Effect?" Am. J. Receptor in the Regulation of REM Sleep, Life Sciences.

Psychiatry, 148(9):1213-17 (1991) (abstract). 66(241999-2012 (2000).Manfredi et al., "Dr. Manfredi and Associates Reply" Am. J. Psy- Monti et al., "Sleep and Waking in 5, 7-DHT-Lesioned ore+chialry, 150(5):845-46 (1993). Pindolol-Pretreated Rats After Administration of Buspirone,Mar. 1, 2012, Communication from European Patent Office, forward- Ipsapirone, or Gepirone, Pharmacology Biochemistry and Behav-

ing Teva Pharmaceutical Industries Ltd.'s Feb. 24, 2012, submission ior, 52(2):305-312 (1995).including DYC1 (Declaration of Professor Boese together with Morrison & Boyld, Organic Chemistry, p. 627, 1974.Enclosures I and 11), DYC2 (Annex III of DYCI), and DYC3 (Rep- Mullins et al., "Effects ofAntidepressants on 5-HT7 Receptor Regu-efition of D3, p. 938 final paragraph, lines 1-3). lation in the Rat Hypothalamus, Neuropsychopharmacology,Mar. 15, 2012, Communication from European Patent Office, for- 21(3):352-367 (1999).warding letter from opponent 04, Egis Gyogyszergyar Nyrt, dated Muraviev, Technology of Medicinal Agents, vol. 1, Moscow, pp.Mar. 2, 2010, regardingAppeal ofEP Patent No. 1330249, including 63-78, 114, 115, 1980.Document D33c (Microtrac Timeline with the part Legacy Microtrac Nagai et al., "Aripiprazoie Ameliorates Phencyclidine-InducedInstrumentation, The Leeds & Northrup Years (1972-1993) with Impairment of Recognition Memory through Dopamine DI andSeries 7991, 7995, and 7997& SVR). Serotonin 5-HT1A Receptors, Psychopharmacology, 202:315-328Mar. 5, 2012, Communication from European Patent Office, forward- (2009).log a letter from opponent 01, Teva Pharmaceutical Industries Ltd., Nanzando's Medical Dictionary, 1990, 17th Ed. p. 1571.

on 08/1 b

ase 1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16 Page 11 of 89 PagelD: 23

US 9,359,302 B2Page 9

(56) References Cited Office Action in US. Appl. No. 13/067,838 dated May 21, 2013.Office Action in U.S. Appl. No. 13/185,879 dated Apr. 30, 2012.

OTHER PUBLICATIONS Office Action in U.S. Appl. No. 13/195,954 dated Aug. 13, 2012.Office Action in U.S. Appl. No. 13/303,265 dated Aug. 20, 2012.

Newman-Tancredi et al., "Clozapine is a partial agonist at cloned, Office Action in U.S. Appl. No. 13/327,607 dated Jun. 1, 2012.human serotonin 5-HTIA receptors, Neuropharmacology, Office Action in U.S. Appl. No. 13/327,607 dated Nov. 8, 2012.35(1):119-121 (1996). Office Action in U.S. Appl. No. 13/327,618 dated Jul. 9, 2013.Newman-Tancredi et al., "Neuropharmacological Profile of Office Action in U.S. Appl. No. 13/426,886 dated May 28, 2013.Bifepmnox: Merits and Limitations in Comparisonwith Other Third- Office Action in U.S. Appl. No. 13/426,886 dated Sep. 26, 2012.Generation Antipsychotics, Current Opinion in Investigational Office Action in U.S. Appl. No. 13/476,758 dated Aug. 7, 2013.Drugs, 8(7):539-554 (2007). Office Action in U.S. Appl. No. 13/476,773 dated Jun.

kiso-b.co.jp/product file/productl.htm, printed. 20, 2007.

20, 2013.Nikkiso, "Microtrac particle distribution a na lyzers, http:// .nik-Office Action in U.S. Appl. No. 13/932,385 dated Dec. 17, 2013.

JulNikolic& Beak, "(R)-(+)-2-(Diphenylhydroxymethyl)pyrro1idine, Ongini et al., "Differential Effects ofDopamine D-1 and D-2 Recep-Organic Syntheses, 74:23 (1997). tor Antagonist Antipsychotics on Sleep-Wake Patterns in the Rat, J.

Notice of Information Disclosure by Third Party issued by the Japa- Phannaco. Exp. Therap., 266:726-731 (1993).nese Patent Office in Japanese Patent Application No. 2007-179275 Ongini et al., "Effects ofRemoxipride, a Dopamine D-2 Antagoniston May 31, 2006. Antipsychotic, on Sleep-Waking Patterns and EEG Activity in RatsNousiainen, Aripiprazole-Analytical Investigation, Dec. 19, 2006. and Rabbits, Psychopharmacology, 107:236-242 (1992).Novelli et al., "A Molecular Investigation Suggests No Relationship Opposition in Indian Patent Application No. IN/PCT/2002/1536Between Obsessive-Compulsive Disorder and the Dopamine 02 dated Jan. 8, 2010, byTorrent PhannaceuticalsLtd., including Exhib-Receptor, Neuropsychobiology, 29:61-63 (1994). its 1A, 3A-3C, and 5 (67 pages).Novelty Search Report from Hungarian Application No. P0600141, Oshiro et al.; "Novel Antipsychotic Agents with DopamineFeb. 19, 2008. Autoreceptor Agonist Properties: Synthesis and Pharmacology ofOct. 14, 2003, Communication from European Patent Office regard- 744-(4-Pheny1-1-piperazinyl)butoxy]-3,4-dihydro-2(1H)-ing EP Patent Application No. 02782507.4. quinolinone Derivatives;" Journal of Med. Chemistry, 41(5):658-Odagaki et al., "5-HT1A Receptor Agonist Properties of 667, (1998).Antipsychotics Determined by [35S] GTPyS Binding in Rat Hip- Otsuka Pharmaceutical Co., Ltd, Additional note in support of inter-pocampal Membranes, Clinical and Experimental Pharmacology locutory injunction application datedMar. 9, 2012, in case No. NSDand Physiology, 34:462-466 (2007). 121/2012 concerning Australian Patent No. 2002226752 andOffice Action (ExParte QuayleAction)in U.S. Appl. No. 12/202,201 2005201772.dated Jun. 1, 2010. Otsuka Pharmaceutical Co., Ltd, Submission in support of interlocu-Office Action (final) in U.S. Appl. No. 13/327,607 dated Jun. 11, tory injunction application dated Mar. 5, 2012, in case No. NSD2013. 121/2012 concerning Australian Patent No. 2002226752 andOffice Action from Japanese Patent Office issued in Japanese Patent 2005201772 (including Annexure A).Application No. 2007-179275 On Apr. 13, 2011. Ozdemir, "Aripiprazole Otsuka Pharmaceutical Co Ltd, CurrentOffice Action from Japanese Patent Office issued in Japanese Patent Opinion in CPNS Investigational Drugs, 2(4105-111 (2000).Application No. 2007-179275 on Oct. 22, 2010. Parada et al., "Rats Self-Inject a Dopamine Antagonist in the LateralOffice Action in Japanese Application No. 2002-560616 dated Nov. Hypothalamus Where ItActs to Increase Extracellular Dopamine in13, 2007. the Nucleus Accumbens, Pharmacology Biochemistry and Behav-Office Action in Taiwanese Patent Application No. 098116881 dated ior, 52(I):179-187 (1995).May 17, 2010. Partial English translation of submission of Sanovel Ilac Sanayi VeOffice Action in U.S. Appl. No. 10/333,244 dated Apr. 29, 2009. Ticaret Anonim Sirketi in opposition to Turkish Patent No. TR2006/Office Action in U.S. Appl. No. 10/333,244 dated Feb. 26, 2007. 0246, dated Feb. 25, 2013.Office Action in U.S. Appl. No. 10/333,244 dated Jun. 11, 2008. Partial translation ofRinsyou SeisinYakuri, "Aripiprazole, JapaneseOffice Action in U.S. Appl. No. 10/876,605 dated Apr. 10, 2009. Journal of Clinical Psychopharmacology, 9:2503-2511 (2006).Office Action in U.S. Appl. No. 10/876,605 dated Aug. 23, 2010. Particulars of Invalidity in case No. NSD 121/2012 for AustralianOffice Action in U.S. Appl. No. 10/876,605 dated Dec. 9, 2009. Patent No. 2002226752 and 2005201772, dated Feb. 10, 2012, byOffice Action in U.S. Appl. No. 10/876,605 dated Mar. 3, 2008. Generic Health Pty Ltd.Office Action in U.S. Appl. No. 10/876,605 dated May 16, 2007. Pecknold et al., "Gepirone and the Treatment ofPanic Disorder: AnOffice Action in U.S. Appl. No. 11/790,504 dated Sep. 29, 2009. Open Study, Journal of Clinical Psychophannacology 13(2):145-Office Action in U.S. Appl. No. 11/790,603 dated Dec. 28, 2009. 149 (1993).Office Action in U.S. Appl. No. 11/790,604 dated May 24, 2010. Perez, Experimental Report on Aripiprazole, Nov. 17, 2003.Office Action in U.S. Appl. No. 11/790,605 dated Apr. 26, 2010. Peny, Manual del Ingeniero Quirnico, vol. 1, 3rd Edition, p. 1239Office Action in U.S. Appl. No. 11/790,606 dated Dec. 11, 2009. (1981).Office Action in U.S. Appl. No. 11/797,019 dated Jan. 7, 2010. Pessina et al., "Aripiprazole augmentation of serotonin reuptakeOffice Action in U.S. Appl. No. 11/797,019 dated Nov. 22, 2011. inhibitors in treatment-resistant obsessive-compulsive disorder: a

Office Action in U.S. Appl. No. 11/797,024 dated Jan. 25, 2010. 12-week open-label preliminary study, Int. Clin. Psychopharmacol.,Office Action in U.S. Appl. No. 11/797,024 dated Nov. 22, 2011. 24:265-269 (2009).Office Action in U.S. Appl. No. 11/797,030 dated Mar. 10, 2010. Petition of Sanovel Ilac Sanayi Ve Ticaret A.S. regarding TurkishOffice Action in U.S. Appl. No. 11/932,795 dated Apr. 15, 2009. patent TR 2006 02467 T4, submitted to the Istanbul 3rd Civil CourtOffice Action in U.S. Appl. No. 11/932,795 dated Dec. 17, 2009. of Intellectual and Industrial Property Rights on Jun. 6, 2013.Office Action in U.S. Appl. No. 11/932,795 dated Feb. 18, 2011. Petrie et al., "Aripiprazole, a new typical antipsychotic: Phase 2Office Action in U.S. Appl. No. 11/932,795 dated Jun. 14, 2010. clinical trial result, European Neuropsychophartnacology 7(SupplOffice Action in U.S. Appl. No. 12/202, 192 dated Jan. 7, 2010. 2):S227 (1997).Office Action in U.S. Appl. No. 12/202,201 dated Oct. 20, 2009. Petrie., "Acuteand Long-Term Efficacyand SafetyofAripiprazole:AOffice Action in U.S. Appl. No. 12/202,208 dated Feb. 24, 2011. NewAtypical Antipsychotic, Schizophrenia Research, 29 (1-2):155Office Action in U.S. Appl. No. 12/202,208 dated Jun. 14, 2010. (1998).Office Action in U.S. Appl. No. 12/830,740 dated May 27, 2011. Pfaus et al., "Role ofDopamine in Anticipatory and ConsummatoryOffice Action in U.S. Appl. No. 13/067,750 dated Jul. 5, 2012. Aspects of Sexual Behavior in the Male Rat, BehavioralOffice Action in U.S. Appl. No. 13/067,750 dated May 22, 2013. Neuroscience, 105:727-743 (1991).Office Action in U.S. Appl. No. 13/067,838 dated Aug. 1, 2012. Planowski et al., "Procesy i aparaty w technologii chemicznej,Office Action in U.S. Appl. No. 13/067,838 dated Aug. 29, 2013. WNT, Warsaw (1974), p. 765-771.



rii

US 9,359,302 B2Page 10

(56) References Cited Robinson et al., "Clinical Effects of the 5HT1A Partial Agonists in

Depression: A Composite Analysis ofBuspirone in the Treatment ofOTHER PUBLICATIONS Depression, J. Clin. Psychopharmacol., 10(3 Suppl):67S-76S

(1990).Pleadings before Arbitrazh Court ofMoscow case No. A40-115364/ Rosenheck et aL, "A Comparison of Clozapine and Haloperidol in12-12-530 by Otsuka Pharmaceutical Co., Ltd. dated Nov. 20, 2012. Hospitalized Patients with Refractory Schizophrenia, The NewPoltronieri et aL, "Antipanic-like Effect of Serotonin Reuptake England Journal of Medicine, 337(12):809-815 (1997).Inhibitors in the Elevated T-maze, Behavioural Brain Research, Rund, BR, "How Do NeurolepticsAffect Cognitive Dysfunctions in147:185 -192(2003). Schizophrenia?, Nord. J. Psychiatry 53(2):121-125 (1999).Pomerantz, "Quinelorane (LY163502), a D2 Dopamine Receptor Rusk et al., "Profile ofthe Selective Dopamine D-2 ReceptorAgonistAgonist, Acts Centrally to Facilitate Penile Erections ofMale Rhesus N-0437: Its Effect on Palatability-and Deprivation-Induced Feeding,Monkeys, Pharmacol, Biochem. Behav., 39:123-128 (1991). and Operant Responding for Food, Physiology & Behavior, 44:545-

Potenza et al., "Olanzapine treatment of children, adolescents, and 553 (1988).Russian Patent Office Submission of Egis Gyógyszergyar Nyrt inadults with pervasive developmental disorders: an open-label pilot

study, J. Clin. Psychopharmacol 19(1):37-44 (1999) (Abstract). Opposition to Russian Patent No. 2259366 (Application No.2003101334), including Enclosure 1, transmitted Oct. 5, 2011.Prinssen et al., "Interactions between neuroleptics and 5-HT1ASachs et al., "The Expert Consensus Guideline Series, Medication

ligands in preclinical behavioral models for antipsychotic andTreatment ofBipolar Disorder 2000, A Postgraduate Medicine Spe-extrapyramidal effects, Psychopharmacology, 144(1): 20-29 (1999). cial Report pp. 1-20, Apr. 2000.

Privitera et al., "Clozapine in a Bipolar Depressed Patient", Am. J. Saha et al., "Safety and Efficacy Profile of Aripiprazole, a NovelPsychiatry, 150(6):986 (1993). Antipsychotic, Schizophr. Res, 36(1 -3):295 (1999).Puel et al., Polymorphism in Fine Organic Processes, LAGEP UMR Sasa et al., "Unique Pharmacological Profile of a NovelCNRS 5007, Universite Lyon 1 ESCPE. Bat. 308G, 43 Bd. du Nov. Antipsychotic Dmg, Aripiprazole (OPC-14597)", CNS Drug11, 1918. F-69622 Villeurbanne, France. Reviews, 3(1):24-33 (1997).Purdon "Long-Term Treatment With Quetiapine Improves Cognitive Schafer et al., "Effects of parkinsonian medication on sleep, JFunction in Schizophrenia, Biol. Psychiatry, 47:42 (2000). Neurol, 247(Suppl 4):IV/24-IV/27 (2000).Rawla, "Basic Principles of Particle Size Analysis, published by Schechter et al, "Thepotential utility of5-HTIAreceptor antagonistsMalvem Instruments, pp. 1-8 (printed from the European Patent inthe treatment ofcognitive dysfunction associated withAlzheimer'sOffice with a timestamp ofJan. 4, 2007). disease, Cum Phann. Des., vol. 8, No. 2, pp. 139-145 (2002)Ray, "CINP 2000—Collegium Internationale Neuro- (Abstract).Psychopharmacologicum 22nd Congress, Drugs, 3(9):1023-1025 Schmidt, Aripiprazol Experimental Report andAttachments I and II.

(2000) (abstract). Dec. 23, 2006.

Realmuto et al. "Clinical Effect ofBuspirone inAutistic Children, J. Scrip News Letter 2000 No. 2580, p. 11 (Oct. 4, 2000).Clin Pyschopharmacol., 9(2):122-125 (1989).

Seidl et al., "Serotonin (5-HT) in brains of adult patients with Down

Syndrome, J. Neural Transm.; 57(supp):221-232 (1999).Remington Fannacia, 1985, 17th Edition, pp. 1911-1920.Seifritz et aL, "The 5-HTIA agonist ipsapirone enhances EEG slow

Remington Farmacia 2000, 20th Edition pp. 824 and 828.wave activity in human sleep and produces apower spectrum similar

Report DYC I ofSiglait Levi signed Jun. 4, 2013, submitted by Tevato 5-HT2 blockade, Neuroscience Letters209:41:44 (1996).Pharmaceutical Industries Ltd. on Jun. 11, 2013, in opposition to EPSerper et al., "Novel Neuroleptics Improve Attentional FunctioningApplication No. 02782507.4/EP Patent No. 1330249. in Schizophrenic Patients: Ziprasidone and Aripiprazole, CNS

Request for declaratory judgment on lack of infringement by Spectrums, 2(8): 56-59 (1997).Generica IlacYes Sanayi Ve Tic A.S. dated Mar. 27, 2013, before the Shapiro et al., "Aripiprazole, a Novel Atypical Antipsychotic DrugIstanbul Court on Duty for Intellectual and Industrial Rights. with a Unique and Robust Pharmacology, Neuropsychopharmacol-Request for Re-examination of Australian Patent No. 2002226752 ogy, vol. 28, pp. 1400-1411 (2003).(Sep. 19, 2008). Sheehan et al., "The Relative Efficacy of High-dose Buspirone andRequest for Re-examination of Australian Patent No. 200233413 Alprazolam in the Treatment of Panic Disorder: A Double-blind(May 1, 2006). Placebo-controlled Study, Acta Psychiatr. Scand., 88(1):1-11Request for Re-examination of Australian Patent No. 2002334413 (1993).(Sep. 1, 2008). Shiah et al., "Cortisol, Hypothermic, and Behavioral Responses toRequest for Re-examination of Australian Patent No. 2005201772 Ipsapirone in Patients with Bipolar Depression and Normal Con-

(Sep. 19, 2008). trots, Neuropsychobiology, 38:6-12 (1998).Response dated Jun. 4, 2009, to Examiner's Re-Examination Report Specification for thethermogravimetric analyzerSDT Q-600, printeddated Jan. 28, 2009, including Third Statement of'VoluntaryAmend- on Jul. 18, 2011.ments. Stahl et al., "Effectiveness of ipsapirone, a 5-HT-1A partial agonist,Response ofMar. 26, 2009, to Re-Examination Report ofAustralian in major depressive disorder: support for the role of5-HT-1A recep-Patent No. 2002334413 datedJan. 28, 2009, including Second State- tors in the mechanism of action of serotonergic antidepressants,ment ofVoluntary Amendments. International Journal of Neuropsychopharmacology 111-18 (1998).Response ofNov. 23, 2006, to Examiner's Re-examination Report of Stahl et al., "Stahl's Illustrated Antipsychotics: Treating Psychosis,Australian Patent go. 2002334413 dated Oct. 10, 2006, including Mania and Depression:' Cambridge University Press (2nd ed. 2010).First Statement ofVoluntary Amendments. Stahl, "Dopamine System Stabilizers, Aripiprazole, and the NextRevised European Patent Office Submission ofTeva Pharmaceutical Generation of Antipsychotics, Part 1—`Goldilocks' Actions atIndustries Ltd. in Opposition to European Patent No. 1330249B1, Dopamine Receptors, J. Clin. Psychiatry 62(11):841-842 (2001).transmitted Apr. 27, 2009. Stahl, "Dopamine System Stabilizers, Aripiprazole, and the NextReynolds, "The new antipsychotics—Some pharmacological aspects Generation ofAntipsychotics. Part 2—Illustrating Their Mechanismof their problems and potential, Expert Opinion on ofAction, J. Clin. Psychiatry 2(12):923-924 (2001).pharmacotherapy 1(2):181-185 (2000). Stahl, Essential Psychopharmacology of Depression and BipolarRhodes, Introduction to Particle Technology, John Wiley & Sons, Disorder, Ed. 1, Cambridge University Press,p. 148, 2000.Chichester, 1998, pp. 69-70. Stam et al., "Human Serotonin 5-HT7 Receptor: Cloning and Phar-Rinsyou Seisin Yakuri, "Aripiprazole, Japanese Journal ofClinical macological Characterisation ofTwo Receptor Variants, FEBS Let-Psychophannacology. 9:2503-2511 (2006). ters 412, pp. 489-494 (1997).Rivas-Vazquez et al., "Atypical Antipsychotic Medications: Pharma- Statement ofClaims before the Arbitrazh Court of Moscow ofEgishcological Profiles and Psychological Implications, Professional Died'Jserdiar Nail'Jvanoshan Mukede Resven'Jtarshashag on rec-

Psychology: Research and Practice, 31(6):628-640 (2000). ognition of the decision of the Federal Service on intellectual prop-

by USPTO from the PIRS Image Database on


US 9,359,302 B2Page 11

(56) References Cited Test Report No. 33 of the X-Ray Diffraction Laboratory of theNational Commission ofAtomic Energy, Ar‘gentina, dated Aug. 25,

OTHER PUBLICATIONS 2003.The Merck Index—Aripiprazole, 2001.

erty ofMay 17, 2012 (referenced in Pleadings beforeArbitrazh Court The Merck Manual, 17th Ed., 1999, pp. 2233-2236.ofMoscow case No. A40-115364/12-12-530 by Otsuka Pharmaceu- The United States Pharmacopeia (LTSP) 29, pp. 2788-2789, (2006).tical Co., Ltd. dated Nov. 20, 2012). Tohen & Zarate, "Antipsychotic Agents and Bipolar Disorder, J.Statement ofGrounds and Particulars byApotex Pty Ltd in opposi- Clin. Psychiatry, 59(suppl. 1):38-48 (1998).tion Australian Patent Application No. 2009233591, dated Feb. 21, Tramontina et al., "Aripiprazole in Juvenile Bipolar Disorder2013. Comorbid with Attention-Deficit/Hyperactivity Disorder: An OpenStatement of Grounds and Particulars dated Apr. 20, 2012, for Aus- Clinical Trialr CNS Speen., 12(10):758-762 (2007).tralian Patent Application No. 2009233591 by Apotex Pty. Ltd. Translation ofOpposition Briefas submitted to the European PatentStatement of Grounds of Opposition dated Apr. 20, 2012, for Aus- Office by patent attorneys Maiwald Patentanwaltsgesellschaft mbH,tralian PatentApplication No. 2009233591 byAlphapharm Pty. Lim- dated Feb. 25, 2008.ited. Tunnicliff, "Molecular Basis of Buspirone's Anxiolytic Action,Statement of Grounds of Opposition filed on Dec. 17, 2010, for Pharmacology & Toxicology, 69:149-156 (1991).Australian. Patent No. 2007201701 by Alphaphann Pty. Ltd. Vieta et al, "Effectiveness of Aripiprazole v. Haloperidol in AcuteStatutory Declaration by James Ellsmore filed in support of the Bipolar Mania, Double-blind, Randomised, Comparative 12-weekAmended Statement of Grounds of Opposition filed Mar. 17, 2011, Trial, British Journal ofPsychiatry, 187:235-242 (2005).for Australian Patent No. 2007201701 by Alphaphann Pty. Ltd Vippagunta et al., "Crystalline Solids, Advanced Drug Delivery(including exhibits JEI-JE8). Reviews 48:3-26 (2001).Statutory Declaration by Julian Parmegiani filed in support of the Vogel, Vogel's Textbook of Practical Organic Chemistry, IncludingAmended Statement of Grounds of Opposition filed Mar. 17, 2011, Qualitative Organic Aanalysis (Longman Scientific & Technical, 4thfor Australian Patent No. 2007201701 by Alphapharm Pty. Ltd reviseded.) 1987, pp. 110-125.

(including exhibits JE1-JE17). Wade & Weller., Handbook ofPHarmaceutical Excipients, American

Statutory Declaration of Bruce Sugriv Singh dated Aug. 21, 2013, Pharmaceutical Association, Washington, and The Pharmaceutical

concerning opposition to Australian Patent Application No. Press, London, 1994, 2nd Ed., pp. 1-2.

2009233591. Wang et al., The Effect of Physical Environment of CrystallizationStatutory Declaration of Bruce Sugriv Singh dated Mar. 14, 2012, Process on the Polymorph ofCiprofioxacin Hydrochloride, School of

concerning the opposition to Australian Patent Application No. Chemical Engineering and Technology, Tianjin University, Tianjin,2007201701 (including Exhibits BSS-3 to BSS-8). 300072, P. R. China, 15th International Symposium onlndustrial

Statutory Declaration of Paula de Bruyn dated Aug. 21, 2013, con- Crystallization 1(2):623-628 (2002).ce 'ng opposition to Australian Patent Application No. Ward et al., "Forebrain serotonin depletion facilitates the acquisition2009233591.

and performance ofa conditional visual discrimination task in rats,Behavioral Brain Research, 100:51-65 (1999).Stellman, Encyclopedia ofOccupational Health and Safety, 4th Ed., Wedd, "Determination ofParticle Size Distribution Using Laser Dif-

p. 7811, 1998. fractionr Educ. Reso. for Part. Techn., 032Q-Wedd (2003).Stigler et al., "Case Report: Aripiprazole for Maladaptive Behavior in Wickenremaratch & Morris, "Aripiprazole Associated with SeverePervasive Development Disordersr J. Child and Adolescent Exacerbation of Parkinson's Disease, Movement Disorders,Psychopharmacology, 14(3):455-463 (2004). 21(9)1538-1539 (2006).Striegel, Aripiprazol Experimental Report, Dec. 21, 2006. Wolfgang Beckmann, "Seeding the Desired Polymorph: Back-Submission of Ratiopharm Gmbh dated Jun. 11, 2013 regarding ground, Possibilities, Limitations, and Case Studies, Chemicalopposition to EP Application No. 02782507.4/EP Patent No. Engineering Department, Chemical Development, Schering AG,1330249. 13342 Berline, Jul. 6, 2000.Submission of Sanovel Ilac Sanyai Ve Ticaret Anonim Siketi in Yamadaet al., Society ofNeuriscience Abstracts 26 (1-2), No. 871.7

opposition to Turkish Patent No. TR2006/0236, dated Feb. 25, 2013. (2000).Submission Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi to the Yau, "Impact ofAdrenalectomy on 5-HT6 and 5-HT7 ReceptorGeneOffice of the Honorable Judge of Istanbul 4th Civil Court for Intel- Expression in the Rat Hippocampus, Molecular Brain Researchlectual and Industrial Property Rights in respect ofthe invalidation of 45:182-186 (1997).the patent with No. TR 2006/02467 T4, datedAug. 2, 2012. Yeung et al., "Efficacy of aripiprazole, a novel antipsychotic, inSubmission ofTeva Pharmaceutical Ltd. dated Jun. 11, 2013, regard- schizophrenia and schizoaffective disorder: Results of a placebo-ing opposition to EP Application No. 02782507.4/EP Patent No. controlled trial with risperidone, Eur. Neuropsychopharm.1330249. 11(Suppl. 3): S259 (2001).Sumiyoshi et al., "Tandospirone, a serotonin-1A agonist, added to York, "The design of dosage forms, in Pharmaceutics: The Science

neuroleptic treatment enhances cognitive performance in schizo- ofDosage Form Design (Aultoned., Churchill Livingston), 1988, pp.phrenia, Database accession No. PREV200200022926, Society for 1-13.Nueroscience Abstracts (2001). Zakrzewsk & Marek, Solid State Characterization of Phannaceuti-Summons to Attend Oral Proceedings from European Patent Office, cats, 2006, pp. 134-135 and 152.

regarding European Patent Application No. 06015782.3 (European Zhang, "Regulation of the Central Opioidergic Nervous System on

Patent No. 1712225), dated Apr. 12, 2010. the Emotional State ofAnxiety and its Possible Mechanisms, ShengTamai et al., "The Clinical Efficacy ofa 5-HT1AAgonist, SM-3997, Li Ke Xue Jin Zhan, 28(1):41-44(1897).in the Treatment of Bulimia, International Journal of Obesity, English translation ofList ofQueries to Panel of Experts by Otsuka14:289-292 (1990). Pharmaceutical Co., Ltd., dated Oct. 21, 2013, to the Office of the

Tamminga & Lahti, "Treatments for chronic psychosis, Dialogues Honorable Judge of Istanbul 3rd Civil Court for Intellectual andin Clinical Neuroscience, 3(4):281-291 (2001). Industrial Property Rights in File No. 2012/200E.Tanninen, Test Report on Aripiprazole, Dec. 19, 2006. English translation ofCubmission ofSanovel Ilac Sanayi Ve Ticaret

Taylor et al., "Treatment of acute mania or hypomania, The South AS. dated Nov. 21, 2013, to the Office of the Honorable Judge ofLondon and Maudsley NTIS Trust 2001 Prescribing Guidelines, 6th Istanbul 3rd Civil Court for Intellectual and Industrial PropertyEdition (2001). Rights in Fi13 No. 2012/200E.Test Report No. 32 of the X-Ray Diffraction Laboratory of the Englsih translation of Ilac Sanayi Ve Ticaret A.S. dated Nov. 21,National Commission of Atomic Energy, Argentina, dated Aug. 20, 2013, to the Office ofthe Honorable Judge ofIstanbul 3rd Civil Court

2003. for Intellectual and Industrial Property Rights in File No. 2012/200E.



US 9,359,302 B2Page 12

(56) References Cited European Patent Office Official Minutes ofOral Proceeding regard-ing Appeal T0801/10 ofOpposition to European Patent No. 1621198,OTHER PUBLICATIONS dated Jul. 8, 2014.

European Patent Office submission ofOtsuka Pharmaceutical Co.,European Patent Office, communication dated Jan. 28, 2014, for- Ltd. regarding Appeal 10801/10 of Opposition to European Patentwarding letter ofopponent Sanovel Ilac Sanayi Ve Ticaret A.S. dated No. 1621198, dated Jun. 6, 2014.Jan. 21, 2014, including exhibits WuW1 and WuVV2.European Patent Office Summons to Oral Proceedings regardingList of Queries to Panel of Experts by Otsuka Pharmaceutical Co., Appeal T0801/10 of Opposition to European Patent No. 1621198,Ltd., dated Oct. 21, 2013, to the Office of the Honorable Judge of dated Feb 242014.Istanbul 3rd Civil Court for Intellectual and Industrial Property,European Patent Office, Interlocutory DecisiRights in File No2012/200E. on in Opposition Pro-

Statutory Declaration of Jayashri Kullcami dated Nov. 21, 2013, ceedings regarding European Patent No. 1330249, dated Feb. 20,concerning the opposition to Australian Patent Application No.

2015.

2009233591, including Exhibit JK-7. European Patent Office, Minutes of Oral Proceedings regardingSubmission of Sanovel Ilac Sanayi Ve Ticaret A.S. dated Nov. 21, Op–position to European Patent No. 1330249, dated Feb. 20, 2015.2013, to the Office ofthe Honorable Judge of Istanbul 3rd Civil Court European Patent Office, Summons to Oral Proceedings regardingfor Intellectual and Industrial Property Rights in File No. 2012/200E. OPPosition to European Patent No. 1330249, dated Jul. 14, 2014.Submission ofquestions to experts ofSanovel Ilae Sanayi Ve Ticaret European Pharmacopoeia 5.0 and 8.0, dated 2005 and 2008.A.S. dated Oct. 21, 2013, to the Office of the Honorable Judge of Expert Report ofSanovel Ilac Sanayi Ve Ticaret A.S. dated Oct. 30,Istanbul 3rd Civil Court for Intellectual and Industrial Property 2014, to the Office ofthe Honorable Judge ofIstanbul 3rdCivil CourtRights in File No. 2012/200E. for Intellectual and Industrial Property Rights in File No. 2012/200,Advisory Action mailed Jun. 2, 2014, in U.S. Appl. No. 13/303,265. regarding Patent No. TR 2006/02467 T4.Australian Government, IPAustralia, Patent Examination Report No. Fujii et al.,"Effects ofClozapine on Cognitive Functioning in Treat-1 for Patent Application No. 2013203248, dated Jul. 28, 2014 ment-Resistant Schizophrenic Patients, J. Neuropsychiatry Clin.Bondolifi et al., on behalf of the risperidone Study Group, Neurosci, vol. 9, pp. 240-245 (1997)."Risperidone Versus Clozapine in Treatment-Resistant Chronic Giron, "Investigations ofPolymorphism and Pseudo-PolymorphismSchizophrenia: ARandomized Double-Blind Study, Am, J. Psychia- in Pharmaceuticals by Combined Thermoanalytical Techniques, J.try, vol. 155, pp. 499-504(1998). Thermal Analysts and Calorimetty, 64: 37-60 (2001).Bradford et al., "Atypical antipsychotic drugs in treatment-refractory Government of India, Patent Office, Communication regardingschizophrenia,"Psychiatty Annals, vol. 28, pp. 618-626 (1998). Patent Application No. 722/KOLNP/2003, dated Aug 29, 2014.Braun et al., "Conformational Polymorphism in Aripiprazole: Prepa- Green et al, "Does Risperidone Improve Verbal Working Memory inration, Stability and Structure ofFive Modifications, J. Pharmaceu- Treatment-Resistant Schizophrenia?" Am, J. Psychiatry, vol. 154, pp.tical Sciences, 98(6): 2010-2026 (2009). 799-804 (1997).Breier et al., "Comparative Efficacy ofOlanzapine and Haloperidol Hagger et al., "Improvement in Cognitive Functions and Psychiatricfor Patients with Treatment-Resistant Schizophrenia, Biol. Psychia- Symptoms in Treatment-Refractory Schizophrenic Patients Receiv-try, vol. 45, pp. 403-411 (1999). ing Clozapine, Biol. Psychiatry, vol. 34, pp. 702-712 (1993).Communication to the European Patent Office, dated Oct. 24, 2014, Hashimoto et al., "Differential changes in serotonin 5-HT IA andAttachment to Submission (Auxiliary Request), regarding EP 5-HT2 receptor binding in patients with chronic schizophrenia,1330249. Psycho-phannacology, vol. 112, pp. S35-S39 (1993).Communication to the European Patent Office, dated Oct. 24, 2014, Jann, "Clozapine, Pharmacotherapy, vol. 11, pp. 179-195 (1991).Attachment to Submission (Main Request), regarding EP 1330249. Japanese Decision of Rejection mailed Aug, 22, 2014, JP 2011-Communication to the European Patent Office, dated Oct. 24, 2014, 133032 DA-05122.Letter regarding the Submission of Additional Experimental Data, Kleven et al., "Modification ofbehavioral effects of8-hydroxy-2-(di-regarding EP 1330249. n-propylamino)tetral in following chronic ethanol consumption in theCommunication to the European Patent Office, dated Oct. 24, 2014, rat: evidence for the involvement of 5-HT1A receptors in ethanolSubmission of Additional Experimental Data, regarding EP dependence, Euro J. ofPharmacology, vol. 281, pp. 219-228(1995).1330249. Lee et al., "Effects of Ciozapine on Cognitive Function in Schizo-Conely et al.,"Evaluation of Treatment>Resistant Schizophrenia, phrenia, J. Clin. Psychiatry, vol. 55 (Suppl. B), pp. 82-87 (1994).Schizophr, Bull., vol. 23, pp. 663-674 (1997). Letter of Opponent (Egis) regarding Opposition to European PatentCourt Judgment, Federal Court of Australia, Bristol-Myers Squibb No. 1330249, dated Nov. 28, 2014.Co. v.ApotexPty. Ltd., regardingAustralian Patent No. 2002334413, Letter ofOpponent (Hexal AG) regarding AppealT2059/13 ofOppodated Jan. 23, 2015. sition to European Patent No. 1712225, dated Apr. 3, 2014.De Vry et al.,"Discriminative stimulus properties ofthe 5-HT recep- Letter ofOpponent (Hexal AG) regarding Appeal T2059/13 ofOppo-tor agonist IA BAY x 3702 in the rat, Euro J. ofPharmacology, vol. sition to European Patent No. 1712225, dated Sep 24, 2014.357, pp. 1-8 (1998). Letter of Opponent (Stada Arzneimittel AG) regarding AppealEnglish translation ofExamination Report inArgentine Patent Appli- T2059113 ofOpposition to European Patent No. 1712225, dated Apr.cation No. P100104973, dated Nov 6, 2014,. 10, 2014.English translation ofExamination Report inArgentine Patent Appli- Letter of Opponent (Teva Pharmaceutical Industries Ltd.) regardingcation No. P110101189, dated Dec. 11, 2014. Appeal T2059/13 of Opposition to European Patent No. 1712225,English Translation of Japanese Decision of Rejection mailed Aug. dated Apr. 14, 2014.22, 2014, JP 2011-133032 DA-05122. Letter of Opponent (Teva) regarding Opposition to European PatentEnglish translation of Office Action in Japanese Patent Application No. 1419776, dated Mar. 2, 2015.No. 2011-133033 dated Aug. 19, 2014. Lucot et al., "Antiemetic effects of flesinoxan in cats: comparisonsEnglish translation ofSubmission of Sanovel Ilac Sanayi Ve Ticaret with 8-hydroxy-2-(di-n-propylamino) tetralin, Euro. J. ofPharma-AS. dated Dec. 29, 2014, to the Office of the Honorable Judge of cology, vol. 253, pp. 53-60 (1994).Istanbul 3rd Civil Court for Intellectual and Industrial Property Markens et al., "Conducting Stability Studies—Recent Changes toRights in File No. 2012/200E, regarding Patent No. TR 2006/02467 Climatic Zone IV, Life Science Technical Bulletin, Issue 13 (2009).T4. Mason et al., "Clozapine has sub-micromolar affinity for 5HT recep-English translation of Technical Exannnation Report in Brazilian tors in human brain tissue, Eur. J. Pharmacol., vol. 221, pp. 397-398Patent Application No. PI 0206237-2, received on Dec. 22, 2014. (1992).European Patent Office Decision of the Technical Board ofAppeals Massimo et al., "5-HT1A Receptor hypersensitivity in migraine isregarding Appeal T08001/10 Opposition to European Patent No. suggested by the m-chlorophenylpiperazine test, NeuroReport vol.1621198, dated Sep. 1, 2014. 9, pp. 2605-2608 (1998).


08/10/2016

rase 1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16 Page 15 of 89 PagelD: 27

US 9,359,302 B2Page 13

(56) References Cited AuIton, Pharmaceutics: The Science of Dosage Form Design,Churchill Livingstone Press, p. 237 (1988).

OTHER PUBLICATIONS Byrn, "Pharmaceutical Solids: A Strategic Approach to RegulatoryConsiderations, Pharmaceutical Research, 12 (7): 945-954 (1995).Meneses et al., "5-HT1A Receptors Modulate the Consolidation of Chou etal., "Occupancy of5-HT1A Receptor by Clozapine Revealed

Learning in Normal and Cognitively Impaired Rats, Eur. J, by Positron EI11101011 Tomography in the Primate Brain, Int. J.Neurosci, vol. 71, pp. 207-218 (1999).Miyamoto et al., "Developing novel antipsychotic drugs: strategies Neuropsychopharmacol., vol. 4 (Suppl. 3), pp. S130, (2000).and goals, Current Opinion in CPNS Investigational Drugs, vol. 2, Communication from the European Patent Office, dated Aug. 24,pp. 25 (2000). 2015, Observations filed by a third party, regarding Application No.Notice ofAppeal, Federal Court ofAustralia, Apotex Ptd. v. Otsuka EP08000358.3.Pharmaceuticals Inc., dated Jun. 10, 2014, Australian Patent No. Communication from the European Patent Office, dated Jul. 22,2009233591. 2015, regarding EP1330249, Appeal No. T0777/15-3.3.02.Office Action (Final) mailed Dec. 20, 2013 in U.S. Appl. No. Drevets et al., "PET Imaging of Serotonin IA Receptor Binding in

13/303,265. Depression, Biol. Psychiatry, vol. 46: p0. 1375-1387 (1999).Office Action (Final) mailed Dec. 5, 2014, in U.S. Appl. No. English translation of Fonyo et al., "Basic Chemical Operations,13/426, 886. National Textbook Publisher Budapest, pp. 901-902 (1998).Office Action (Final) mailed Jun. 25, 2014, in U.S. Appl No. European Phannacopoeia 5.4: Residual Solvents, pp. 507-515.13/932,385. Fonyo et al., "Basic Chemical Operations, National Textbook Pub-Office Action in Japanese PatentApplication No. 2011-133033 dated lisher Budapest, pp. 901-902 (1998).Aug. 19, 2014. Gennaro, Remington: The Science and Practice of Pharmacy, 20thOhmori et al., "Late Phase II Study ofAripiprazole for Schizophre- Edition, Lippincott Williams & Wilkins, pp. 656-657 (2001).nia, JP Journal of clinical Psychopharmacology, vol. 9, No. 2, Feb. Goodwin, F.K. and Jamison, KR., Manic-Depressive Illness, Oxford2006. University Press, pp. 420-422 (1990).Rasmussen et al.,"Chapter 1. Recent Progress in Serotonin (5-HT)1 Hilty et al., "A Review of Bipolar Disorder Among Adults, Psychi-A Receptor Modulators, in Annual Reports in Medicinal Chemistry, atric Services, vol. 50(2): pp. 201-213 (1999).vol. 30, pp. 1-9 (1995). Lachman et al., The Theory and Practice ofIndustrial Pharmacy, 3rdSharma et al„"The Cognitive Efficacy of atypical antipsychotics in Edition, Lea & Febiger, pp. 181-182 (1986).schizophrenia, J. of Clinical Psychopharm., vol. 18, pp. 12S-I9S Letter ofAppeal by Fermion, regarding Opposition to EP1330249,(1998). dated Jun. 17, 2015.Submission of Opponent (Egis) regarding Opposition to European Letter ofAppeal byPolpharma, regarding Opposition to EP1330249,Patent No. 1330249 (Results ofwater uptake measurements), dated dated Jul. 2, 2015.Oct. 30, 2014. Mahmood et al., "Serotonin and bipolar disorder, J. Affective Dis-Submission of Opponent (Egis) regarding Opposition to European orders, vol. 66: pp. 1-11 (2001).Patent No. 1330249 (Solid state characterization of aripiprazole Mason et al., "Clozapine has sub-micromolar affinity for 5-HT1A

samples), dated Nov. 26, 2014. Receptors in Human Brain Tissue, Eur. J. Pharmacol., vol. 221: pp.Submission of Opponent (Egis) regarding Opposition to European 397-398 (1992).Patent No. 1330249 (Sununaty of laboratory experiments on crystal- Miller et al., "Are Antidepressants Less Effective in the Acute Treat-lization and drying of aripiprazole), dated Mar. 11, 2014. ment ofBipolar I Compared to Unipolar Depression?, J. AffectiveSubmission of Sanovel Ilac Sanayi Ve Ticaret A.S. dated Dec. 29, Disorders, vol. 67: pp. 141-146 (2001).2014, to the Office ofthe Honorable Judge of Istanbul 3rd Civil Court Notice ofAppeal, submittedby Dowa, dated 2015, Trial Briefregard-for Intellectual and Industrial Property Rights in FileNo. 2012/200E, ing Korean Patent No. 10-0763288.

regarding Patent No. TR 2006/02467 T4. Notice of Appeal, submitted by Eishin, dated 2015, Trial Brief

Sumiyoshi et al., "Effect ofadjunctive treatment with serotonion- la regarding Korean Patent No. 763288.

agonist tandospirone on memory functions in schizophrenia, J. Clin. Office Action in U.S. Appl. No. 13/426,886 dated May 15, 2015.

Pharmacol., vol. 20, pp. 386-388 (2000). Office Action in U.S. Appl. No. 14/624,595 dated Jun. 9, 2015.TA Instruments, "Thermal Analysis Application Brief: Kinetics of Shin-Shiah et al., "Cortisol, Hypothennic, and Behavioral ResponsesDrying by Therrnogravimetric Analysis, No. TA-134. to Ipsapirone in Patients with Bipolar Depression and Normal Con-U.S. Pharmacopeia, "X-Ray Diffraction, Section 941: 2088-2089 trols, Neuropsychobiology, vol. 38(6): pp. 6-12 (1998).(2002). Tohen et al., "Effect ofOlanzapine in Acute Bipolar Mania, Arch.Wolffet al., "Effects ofa 5-HT receptor agonist on acute and delayed Gen. Psychiatry, vol. 57 (9): pp. 841-849 (2000).IA cyclophosphamide-induced vomiting, Euro J. ofPharmacology,vol. 340, pp. 217-220 (1997). cited by examiner


Tease 1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16 Page 16 of 89 PagelD: 28

U.S. Patent Jun. 7, 2016 Sheet 1 of 31 US 9,359,302 B2

00Aulanomuoonu3H1

cot'.co

co

c7i

co -E0 6

LI.,2

mco 6

Ro.

co

co a ri)

(Art) via4

a

(0.)3UnIvEl3d1/131.


!Case 1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16 Page 17 of 89 PagelD: 29


0

Co)

iieL

CO

CZ)


pease 1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16 Page 18 of 89 PagelD: 30


a

cf)

L.,co 0 cb

a cv

•1••••••

.040.^

00

1.0C11

[sdo]AlISN3INI

Image Database on 08/10/2016

Copy provided by USPTO from 08/10/2016

rCase 1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16 Page 19 of 89 PagelD: 31


CD

C‘J

CO

cl•

MINIMS

-Lo

7E

CO

0)

-0

the PIRS Image Database on



a

(v)

c‘i

0

U—

c)a

1 qa

14

0 0 0 0 0 0 0CI 0 0 0 0 00 LO Cr la 0 LOVI CV CV T— 1--

Esdo] KLISN3INI

Copy provided by USPTO from the PIRS Image Database on 08110/2016

"Case 1:16-cv-05400-JBS-KMW Document 1-3 Filed 09102716—Fralle-21-M3712"81


%)A1::11.31,11AVIJ 001A11:13H1tr) Ix)c‘l Lr) N.C1.1 Iii CO rs.

I s I CDLr)co

N.coNCO

\s".....r...P..:

LO Nal* ci

C P

NI-1,

inin (NI

Sil 6N

CO•aeco .671cm

a)1••• L11

F:co

a -.4-...6

N.

I N.

I I F C`5;

I 1 Ic:12 rf,

6;

(A 71) VIO

0 tr)ci MICILVE134:31/133_


6") 2



I. it? CD

0 CV

LL

1 C)q

0 8cz,

[sc] A1ISNLNI

by USPTO from the PIRS Image Database on 08/10/2016

!ease 1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16 Page 23 of 89 PagelD: 35


Ald.131AllAVUOOIAIU3.1.

(NI

CO

ej. 017CO

CV

ea

CO

LL

0303

00

1.0

a

IX) rY)

7

(A 71) via

(00) 31:1111.Vki3d


fr'*!"-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16 Page 24 of 89 PagelD: 36


o

0LL

.17


J

1Th



a

CD0

0 4.4

Um=

tI. I. 1 IIII..

a o a o ao o o o o1.• o

(sdol AllSNaLNI


Z BEL

ruse 1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16 Page 26 of 89 PagelD: 38


ss-sstet* 994

9Z 01 '026

ZelL9689

L 1

Z9 '09L917- 909

00190

69 'Vie""*"."4"."7.......... 99 'S9616 666 0

L9 '1501 or .ovo t 0

'261-7-1149 'LI lt

91.11911SC •89il

1611

'SirL06 69It

IS

St 'SOK Se '61.6199 "SZP

SO '61.1

1, 2 '0661 8Lt1 'Oat

••16 '429L

62 'Mt'rm..

(ND OS

LL

8to

gs LUZso .con

""-le....gaa111 9g '9E6Z8

1616

0

0otiolt.i..iiiIatilit 8

8 8 gg pg.) u„,, to, verv.

soutn.4. pusue.41%

Copy provided by USPTO from the PIRS Image Database on 0811012016



0

r

oEl

MIMS=

I ........040.n?

^1•111S.

I.

rem& 1

1i. k in.-4

css


^^^^^••AMM,

^••^IV ..e.•-••••

•••••••10.[P



Abil3INIAVU001Altthal

1.17 CJ 1.17 Lf7

C*7

co

t.0

f-'

cc;0.)

LLIa) cccu D

CC

111

Za) I—

LLI

tr) CV C7i s I

(A 7./ via

0 ID 0 LCI C70 C.I 1.1 0

I I I I I

UP-UPY0 Ma

Copy provided by USPTO from the PIRS Image Database on 08/10/2016bah—

rse 1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16 Page 29 of 89 PagelD: 41



J

1

LL.

-rime 1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16 Page 30 of 89 PagelD: 42


...W.'. 0

a

I.C). Utta

t TIMM 0 Cboto

C.4

I. 0=Ems,

Um.

a

i 1 I. I I. t. 11-.o o a o

[sdo] A.1.15N]l.N1t

i.




i

.r.._, 34 '939 01 CI

Ira1 99 -969

1

SP 'OILr

.0Z gLL

GO -IN

C.......„09 7.96

.._ei. '801 '966 0

0LC 'WU 0

Thet

35 'CIA

.9i. 0.

St 'Mal69 *eat

sL 'gar

i --C___...___VL "LLP lL9 '9441

I- -6391 gi 4--

Ot 'tatan

1 h

CD. ....9C 'Mt In

(...D. cc

c>LL-

8e4

8inc...,

'6gL3...„90

...........te '0;$49.eou0

-861. 6019 c*

09 'OM

00tocn

0•111•11I IIIIIIIII Ili 11701/1141711.411111.11.11111 88 0 a o a 0 a a 0 0

o) oa r-• co in Tr c, c.1

e*UO11.!WSUe.1196

:i 4:•.1- Copy provided by USPTO from the PIRS Image Database on 0811012016

se 1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16 Page 32 of 89 PagelD: 44


0

—8a4"•CD

00

the PIRS Image Database on 08/10/2016

1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16 Page 33 of 89 PagelD: 45


r.1

I

01.1, Ca CI a, fft. CriCr) Ca I CO ea

ICV Ca Ill a,

1 1 I

A V J. a

cs csCa CMCa

(O.) 31=111.1.\/1:13dWal.


'rase1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16 Page 34 of 89 PagelD: 46


rsa

m"."-•

aro

aro

4:3

'2




aa

11^11

C L:

041:0r••

LL

a

a a 0 0 aa a a o

o 0 0 0es 4..

[sclo] AlISN3INI

Copy provided by USK° from the PIRS Image Database on 08/10/2016



6511141 .8SO US;

1....

hlb '9Z91

CC 11691 LIc

'1."'.3..41/

c\I i

0 0,

3.

t.l.C•1

tt)C•1

111

001.1014.1WSUUJJA


'sm.-690

flt '4ZS C

'61,S

16 .1.99CL IGO

L 'OLL--ts'ret

VS 'CU

SP *gee

rune

ZIS os• gte 61 '696

OS •61,0L

Z6 lie

-10ZL

16 'IntOTOS Z

'OCC t

S6.0131, 1 1ft 1Le

9L'OLSI.Zfl '1341/1

11Ptcl

SO US;

...161Z91CC 11691

lit1LZLig

to 'CO6Z

L '6SOC

tio# I 1'mi/it. 1 I ;I0 0 0 0 0 0CO r4-

lpira-se 1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16 Page 37 of 89 PagelD: 49


AEL1JV4IAVEIDOW1=131

tO to C>

7

II

03113

044r-

CDas.ar

ea020)

er3

.6C\I 144 E

CN.r-

CDLL

aS

Is ir, 02 02 LO 1...C=I

1 I i I

(A71) V-La

c• La tz) toc^ to CO 04CV

(go) atinivaadviai.

1.1\- Copy provided by USPTO from the PIRS Image Database on 0811012016



in

CO

oIi

C\J1- I

•71

CI




a

I 1t. 1, IIa a a ao a a ao a a a.r .9 9.

[sd3] ADSN3IN I


08/10/2016



0

0

imam

8o

.CtC\

(t.D

8u-,

I. 0F,

0

C.

0

8sr

SOU94.14WSUBJ196


I

I.1

C.--SI:HS 06 LOL.......60 -SCL

c.... ZZ 'ILLZ6 '6OL

c.. 09 '6Z9Z6 '098

9Z "C96'----2.----` ....--.''""---oo'••Iioat I

•---...__...______.....9C '9C0i II

99 IlLI I99' I.5 Lt.

C Cal ttri..9Z I,l.e'1121

nr ...EL 0061.

..._.litrawr______________,.0'1901

—19 *C6Y1 yg tut i99 IL9I

^...-9L'Elat..L t "GGL01M

CL 'CCU99 'ME

'MC-

te...15......SO '96 IC

it...111.1111.1oilitItial, iiliti111^11^1114710 0 0 0 0 0 0 0 0c3 cn

1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16--Page 41 of 89


(%)A1113INIANi81001/111:13H.L.

0 Cr? u?ix CD

I 0,

CV

CMco

2LL

I j 0Ln cm 7 I 1..7' 0

(A 71) NYICI

o a a a o ar--- cv) a) is),'c".1

(a) al fILVE13d WM_




I I--

C\J



US. Patent Jun. 7, 2016 Sheet 28 of 31 US 9,359,302 B2

7,COC\I a

a

a MI0 m1,1

LLammo

0 0 a 0 a aa 0 a 0

[sdo] AlISNBINI

provided by USPTO from the PIRS Image Database on 08110/2016

rse

Copy provided by



8

8

0-"St 'LLVI

01

0t0

VLSII l *C691.

69 '9691.

0

0) L.0

1•••••

LL0

C

8

0

CNI 1(.5

tr)C^1

80.7

0

Co]

00o<t

aottall!tusue

USPTO from the Pitt image uatabase on 08/10/2016

at .zet,az •sap

eet, 0 L •9Z9

'Les'049

86 'VL969 'CLL

9C 'SRLC9 '98L

'L99

9Z 'LV679G

LL 'OCOPL 'Stan

'96t„.„011189 I

...69 1, 6 L L

IV 'LVZ IIL 'OM

...Zt '806tVet

00 •LLCI.99 'OK

LO '901, L

-.St 'CCP..'Mt

C9 VLSII I, *C691.

69 1„Z9

'ZI.fg

c.° VP 1.46Z

09 '490C9Z 'OM

68 *Z0Ze

tasiet•it.1.1111.1111111611tlej11•11111.111161•1111'0I•••• 8 0 0

tO0 0 0

r-

ease 1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16 Page 45 of 89 PagelD: 57


(%)A1:113WINVE1901/111713H1Lo

in to r) co oc-i ci) 93 c'

coI i i i co

P

COcc, E

0 1—

U— F-

0041CNI

CO

t I c3 10 CO C I Cil CI?

(A 71 viat i

0 CD 0 0 0 0r.c. 0) 10 I-N 7-

b.) 3b111.1.VEGclill31


se

Copy provided

1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16- Page 46 of 89 PagelD: 58


0

[sdolAIISN3INI


Toro0.C •-..-1

a Z.

CD c..4

IL

1 2

Copy provided


US 9,359,302 B2

LOW HYGROSCOPIC ARLPIPRAZOLE DRUG processing of these hygroscopic crystals, the potential forSUBSTANCE AND PROCESSES FOR THE absorbance of moisture during storage and handling would

PREPARATION THEREOF adversely affect the dissolubility of aripiprazole drug sub-stance. Thus shelf-life of the product could be significantly

RELATED APPLICATIONS 5 decreased and/or packaging costs could be significantlyincreased. It would be highly desirable to discover a form of

This application is a continuation of U.S. patent applica- aripiprazole that possessed low hygroscopicity thereby facili-tion Ser. No. 13/350, 117, filed Jan. 13, 2012, which is a tating pharmaceutical processing and formulation operationscontinuation ofU.S. patent application Ser. No. 10/333,244, required for producing dosage units of an aripiprazolewhich is a §371 of International Application No. PCT/JP02/ 10 medicinal product having improved shelf-life, suitable dis-09858, filed Sep. 25, 2002, which claims priority of Japanese solubility and suitable bioavailability.PatentApplication Nos. JP 2001-290645, filed Sep. 25, 2001, Also, Proceedings ofthe 4th Japanese-Korean Symposiumand JP 2001-348276, filed Nov. 14, 2001, and of Canadian on Separation Technology (Oct. 6-8, 1996) state that, anhy-Patent Application No. CA 2379005, filed Mar. 27, 2002, the drous aripiprazole crystals exist as type-I crystals and type-IIcontents of all of which are incorporated by reference. 15 crystals; the type-I crystals of anhydrous aripiprazole can be

prepared by recrystallizing from an ethanol solution of arip-DETAILED DESCRIPTION OF THE INVENTION iprazole, orby heating aripiprazolehydrate at 80° C.; and the

type-II crystals ofanhydrous aripiprazole can be prepared by1. Field of the Invention heating the type-I crystals ofanhydrous aripiprazole at 130 toThe present invention relates to an improved form of arip- zo 140° C. for 15 hours.

iprazole having reduced hygroscopicity and processes for the By the aforementioned methods, anhydrous aripiprazolepreparation of this improved form. type-II crystals having high purity can not be easily prepared

2. Background of the Invention in an industrial scale with good repeatability.Aripiprazole, 7-1444-(2,3-dichloropheny1)-1-piperazi-

ny1]-butoxyl-3,4-dihydro carbostyril or 7-{444-(2,3-dichlo- 25 SUMMARY OF THE INVENTIONropheny1)-1 -piperazinyl] -butoxy -3,4 -dihydro-2(1H)-quinolinone, is an atypical antipsychotic agent useful for the Thus according to the present invention is provided a formtreatment ofschizophrenia (U.S. Pat. No. 4,734,416 and U.S. ofaripiprazole having reduced hygroscopicity and which isPat. No. 5,006,528). Schizophrenia is a common type of more amenable to pharmaceutical processing and formula-psychosis characterized by delusions, hallucinations and 30 tion. The inventors of the present invention have discoveredextensive withdrawal from others. Onset of schizophrenia that this reduced-hygroscopic form ofAripiprazole is a crys-typically occurs between the age of 16 and 25 and affects 1 in talline substance defined herein as Anhydrous Aripiprazole100 individuals worldwide. It is more prevalent than Alzhe- Crystals B. A particular process for the preparation of thisimer's disease, multiple sclerosis, insulin-dependent diabetes anhydrous crystalline substance has also been discovered andand muscular dystrophy. Early diagnosis and treatment can 35 comprises yet another aspect of the present invention. Par-lead to significantly improved recovery and outcome. More- ticularly, itwas discoveredas partofthe present inventionthatover, early therapeutic intervention can avert costly hospital- in order to produce Anhydrous Aripiprazole Crystals B hav-ization. ing the desired pharmaceutical properties and utilizing the

According to Example 1 of Japanese Unexamined Patent most efficient process, Hydrate A, as defined herein, wouldPublication No. 191256/1990, anhydrous aripiprazole crys- ao have to serve as the intermediate. It was also discovered thattals are manufactured for example by reacting 7-(4-bromobu- a particular sequence ofprocessing had to be implemented intoxy)-3,4-dihydrocarbostyril with 1-(2,3-dichlorophenylpip- order to form Hydrate A. It was discovered that the prepara-eradine and recrystallizing the resulting raw anhydrous tion ofHydrate A required milling what is defined herein as

aripiprazole with ethanol. Also, according to the Proceedings Conventional Hydrate. Then, Hydrate A can be transformedof the 4th Japanese-Korean Symposium on Separation Tech- 45 into Anhydrous Aripiprazole Crystals B through suitablenology (Oct. 6-8, 1996), anhydmus aripiprazole crystals are heating as defined herein. Surprisingly, if the Conventionalmanufactured by heating aripiprazole hydrate at 80° C. How- Hydrate is first heated and then milled, serious agglomerationever, the anhydrous aripiprazole crystals obtained by the sets in rendering the processing commercially unsuitable.aforementioned methods have the disadvantage ofbeing sig- An object of the present invention is to provide novelnificantly hygroscopic. so anhydrous aripiprazole crystals.

The hygroscopicity of these crystals makes them difficult Moreover, another object of the present invention is toto handle since costly and burdensome measures must be provide anhydrous aripiprazole crystals which neither easilytaken in order ensure they are not exposed to moisture during convert into hydrates nor substantially decrease the originalprocess and formulation. Exposed to moisture, the anhydrous solubility, evenwhen a pharmaceutical composition compris-form can take on water and convert to a hydrous form. This 55 ing anhydrous aripiprazole is stored fora long period oftime.presents several disadvantages. First, the hydrous forms of Further object ofthe present invention is to provide prepa-aripiprazole have the disadvantage ofbeing less bioavailable ration methods, in order to obtain anhydrous aripiprazoleand less dissoluble than the anhydrous forms ofaripiprazole. crystals having high purity in an industrial scale with goodSecond, the variation in the amount ofhydrous versus anhy- repeatability.drous aripiprazole drug substance from batch to batch could 60 The present inventors have conducted research worksfail to meet specifications set by drug regulatory agencies. aimed to attain the aforementioned objects. In the course ofThird, the milling may cause the drug substance, Conven- the research, they have found that the desired anhydroustional Anhydrous Aripiprazole, to adhere to manufacturing aripiprazole crystals can be obtained when a well-knownequipment which may further result in processing delay, anhydrous aripiprazole is heated at the specific temperature.increased operator involvement, increased cost, increased 65 Further, the present inventors have found that the desiredmaintenance and lower production yield. Fourth, in addition anhydrous aripiprazole crystals can be obtained from recrys-to problems caused by introduction of moisture during the tallization of a well-known anhydrous aripiprazole by using



US 9,359,302 B23 4

the specific solvents. Moreover, the present inventors found FIG. 23 shows an 1H-NMR spectrum (DMSO-c16, TMS) ofthat the desired anhydrous aripiprazole crystals can be the type F crystals of anhydrous aripiprazole obtained inobtained by suspending a well-knownanhydrous aripiprazole Example 15.in the specific solvent, and heating thus obtained suspension. FIG. 24 shows a powderX-ray diffraction spectrum ofthe

The present invention thus completed on the basis ofthese 5 type F crystals of anhydrous aripiprazole obtained infindings and knowledge. Example 15.

FIG. 25 shows an IR spectrum of the type F crystals ofBRIEF DESCRIPTION OF THE DRAWINGS anhydrous aripiprazole obtained in Example 15.

FIG. 26 shows thermogravimetric/differential thermalFIG. 1 is a thermogravimetric/differential thermogram of 10 analysis endothermic curve of the type G crystals of anhy-

the Aripiprazole Hydrate A obtained in Example 1. thous aripiprazole obtained in Example 16-b).FIG. 2 shows the III-NMR spectrum (DMSO-d6, TMS) of FIG. 27 shows an

I- H-NMR spectrum (DMSO-d6, TMS) ofthe Aripiprazole Hydrate A obtained in Example 1. the type G crystals of anhydrous aripiprazole obtained in

FIG. 3 is a powder x-ray diffraction diagram of the Arip-15 Example 16-b).

iprazole Hydrate A obtained in Example 1. FIG. 28 shows a powder X-ray diffraction spectrum oftheFIG. 4 shows the '1-1-NMR spectrum (DMSO-d,, TMS) of type G crystals of anhydrous aripiprazole obtained in

the Anhydrous Aripiprazole Crystals B obtained in Example Example 16-b).2. FIG. 29 shows an IR spectrum of the type G crystals of

FIG. 5 is a powder x-ray diffraction diagram ofthe Anhy- 20 anhydrous aripiprazole obtained in Example 16-b).drous Aripiprazole Crystals B obtained in Example 2. FIG. 30 shows a thenuogravimetric/differential thermal

FIG. 6 is a thermogravimetric/differential thermogram of analysis endothermic curve of the glass form of anhydrousthe aripiprazole hydrate obtained in Reference Example 3. aripiprazole obtained in Example 16-a).

FIG. 7 is a powder x-ray diffraction diagram of the arip- FIG. 31 shows a powderX-ray diffraction spectrum oftheiprazole hydrate obtained in Reference Example 3. 25 glassy state of anhydrous aripiprazole obtained in Example

FIG. 8 shows thermogravimetric/differential thermal 16-a).analysis endothermic curve of the type C crystals of anhy-drous aripiprazole obtained in Example 11. DETAILED DESCRIPTION OF THE INVENTION

FIG. 9 shows an '1-1-NMR spectrum (DMSO-c16, TMS) ofthe type C crystals of anhydrous aripiprazole obtained in 30 According to first embodiment of the first aspect of theExample 11.

present invention is provided Hydrate A of aripiprazoleFIG. 10 shows a powder X-ray diffraction spectrum ofthe wherein said Hydratehas a powderx-raydiffraction spectrum

type C crystals of anhydrous aripiprazole obtained in which is substantially the same as the powder x-ray diffrac-Example 11. tion spectrum shown in FIG. 3.

FIG. 11 shows an IR spectrum of the type C crystals of 35According to another embodiment ofthe first aspect oftheanhydrous aripiprazole obtained in Example 11.

present invention is provided Hydrate A of aripiprazoleFIG. 12 shows a solid 13C-NMR spectrum of the type Ccrystals of anhydrous aripiprazole obtained in Example 11. wherein said Hydrate has powder x-ray diffraction character-

FIG. 13 shows a the ogravimetric/differential thermal istic peaks at 20=12.6°, 15.4°, 17.3°, 18.0°, 18.6°, 22.5° and

analysis endothermic curve of the type D crystals of anhy- ao 24.8°.

drous aripiprazole obtained in Example 12 or Example 13. According to another embodiment ofthe first aspect ofthe

FIG. 14 shows an11-1-NMR spectrum (DMSO-c16, TMS) of present invention is provided Hydrate A of aripiprazolethe type D crystals of anhydrous aripiprazole obtained in wherein saidHydrate has particular infraredabsorption bands

Example 12 or Example 13. at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and 784FIG. 15 shows a powder X-ray diffraction spectrum of the 45 cra-' on the IR (KBr) spectrum.

type D crystals of anhydrous aripiprazole obtained in According to another embodiment ofthe first aspect oftheExample 12 or Example 13. present invention is provided Hydrate A of aripiprazole

FIG. 16 shows an IR spectrum of the type D crystals of wherein said Hydrate has an 11-1-NMR spectrum which isanhydrous aripiprazole obtained in Example 12 or Example substantially the same as the '11-NIvIR spectrum (DMSO-ds,13. 50 TMS) shown in FIG. 2.

FIG. 17 shows a solid '3C-NMR spectrum of the type D According to another embodiment ofthe first aspect ofthecrystals ofanhydrous aripiprazole obtained in Example 12 or present invention is provided Hydrate A of aripiprazoleExample 13. wherein said Hydrate has an

1- H-NMR spectrum (DMSO-d6,FIG. 18 shows a thermogravimetric/differential thermal TMS) having characteristic peaks at 1.55-1.63 ppm (m, 2H),analysis endothermic curve of the type E crystals of anhy- 55 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56drous aripiprazole obtained in Example 14.

1010111 (m 4H+DMSO) 2.1-1),2.97 ppmFIG. 19 shows an H-NMR spectrum (DMSO-d6, TMS) of78 ppm (t 3=7.4 Hz,2thetype E crystals of anhydrous aripiprazole obtained in (brt, 3=4.6 Hz, 4H), 3.92 ppm (t, 3=6.3 Hz, 2H), 6.43 ppm (d,

J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, 3=2.4 Hz, 1H), 7.04Example 14.FIG. 20 shows a powder X-ray diffraction spectrum ofthe 60 ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32

type E crystals of anhydrous aripiprazole obtained in ppm (m, 211) and 10.00 ppm (s, 1H).Example 14. According to another embodiment ofthe first aspect ofthe

FIG. 21 shows an IR spectrum of the type E crystals ef present invention is provided Hydrate A of aripiprazoleanhydrous aripiprazole obtained in Example 14. wherein said Hydrate has an endothermic curve which is

FIG. 22 shows a thermogravimetric/differential thermal 65 substantially the same as the thermogravimetric/differentialanalysis endothermic curve of the type F crystals of anhy- thermal analysis (heating rate 5° C./min) endothermic curve

drous aripiprazole obtained in Example 15. shown in FIG. 1.


5 6


US 9,359,302 B2

According to another embodiment ofthe first aspect of the stance for 24 hours ina dessicatormaintained at a temperaturepresent invention is provided Hydrate A of aripiprazole of60° C. and a humidity level of 100%.wherein said Hydrate has a mean particle size of 50 pm or According to a first embodiment ofthe fourth aspect ofthe

less, present invention is provided aripiprazole drug substance of

According to another embodiment ofthe first aspect ofthe 5 low hygroscopicity wherein said low hygroscopicity is a

present invention is provided Hydrate A of aripiprazole moisture content of 0.4% or less after placing said drug sub-

wherein said Hydrate has a mean particle size of 40 inn orstance for 24 hours ina dessicator maintained at a temperature

less. of 60° C. and a humidity level of 100%.According to another embodiment ofthe fourth aspect ofAccording to another embodiment ofthe first aspect ofthe

present invention is provided Hydrate A of aripiprazole io the present invention is provided aripiprazole drug substanceof low hygroscopicity wherein said low hygroscopicity is awherein said Hydrate has a mean particle size of 35 pm or

lessmoisturecontent of 0.25% or less after placing said drugsubstance for 24 hours in a dessicator maintained at a tem-

According to another embodiment ofthe first aspect oftheperature of 60° C. and a humidity level of 100%.

present invention is provided Hydrate A of aripiprazole is According to another embodiment of the fourth aspect ofwherein said Hydrate has a mean particle size of 30 gm or the present invention is provided aripiprazole drug substanceless, of low hygroscopicity wherein said low hygroscopicity is a

According to another embodiment ofthe first aspect of the moisture content of 0.15% or less after placing said drugpresent invention is provided Hydrate A of aripiprazole substance for 24 hours in a dessicator maintained at a tem-wherein said Hydrate has a mean particle size of 25 pm or 20 perature of 60° C. and a humidity level of 100%.less. According to another embodiment of the fourth aspect of

According to another embodiment ofthe first aspect of the the present invention is provided aripiprazole drug substance

present invention is provided Hydrate A of aripiprazole of low hygroscopicity wherein said low hygroscopicity is a

wherein said Hydrate has a mean particle size of 20 pm or moisture content of 0.10% or less after placing said drugless. 25 substance for 24 hours in a dessicator maintained at a tern-

According to another embodiment ofthe first aspect ofthe perature of 60° C. and a humidity level of 100%.

present invention is provided Hydrate A of aripiprazole According to another embodiment of the fourth aspect ofwherein said Hydrate has a mean particle size range of40 to the present invention is provided aripiprazole drug substance10 pm. of low hygroscopicity wherein said low hygroscopicity is a

According to another embodiment of the first aspect of the 30 moisture content of 0.05% or less after placing said drugpresent invention is provided Hydrate A of aripiprazole substance for 24 hours in a dessicator maintained at a tem-

wherein said Hydrate has a mean particle size range of36 to perature of60° C. and a humidity level of 100%.14 jun. According to another embodiment ofthe fourth aspect of

According to a second aspect of the present invention is the present invention is provided aripiprazole drug substanceprovided a process for the preparation ofHydrate A wherein 35 of low hygroscopicity wherein said low hygroscopicity is a

said process comprises the steps of milling Conventional moisture content of 0.04% or less after placing said drugHydrate. substance for 24 hours in a dessicator maintained at a tem-

According to a first embodiment ofthe second aspectofthe perature of60° C. and a humidity level of 100%.

present invention is provided a process for the preparation of According to another embodiment ofthe fourth aspect of

Hydrate A comprising the steps of milling Conventional 40 the present invention is provided aripiprazole drug substance

Hydrate wherein said milling is performed by a milling of low hygroscopicity wherein said drug substance is Anhy-machine. drous Aripiprazole Crystals B as defined herein.

According to another embodiment of the second aspect of According to another embodiment of the fourth aspect ofthe present invention is provided a process for the preparation the present invention is provided aripiprazole drug substanceof Hydrate A comprising the steps of milling Conventional as of low hygroscopicity wherein said drug substance has a

Hydrate wherein said milling machine is an atomizer, pin powder x-ray diffraction spectrum which is substantially the

mill, jet mill or ball mill, same as the powder x-ray diffraction spectrum shown in FIG.

According to another embodiment of the second aspect of 5.the present invention is provided a process for thepreparation According to another embodiment of the fourth aspect ofof Hydrate A comprising the steps ofmilling Conventional so the present invention is provided aripiprazole drug substance

Hydrate wherein said milling machine is an atomizer. of low hygroscopicity wherein said drug substance has a

According to another embodiment of the second aspect of powder x-ray diffraction spectrum having characteristicthe present invention is provided a process for the preparation peaks at 213=11.0°, 16.6°, 19.3°, 20.3° and 22.1°.of Hydrate A comprising the steps ofmilling Conventional According to another embodiment ofthe fourth aspect of

Hydrate wherein said milling machine is an atomizer using a 55 the present invention is provided aripiprazole drug substancerotational speed of5000-15000 rpm for the main axis, a feed of low hygroscopicity wherein said drug substance has par-rotation of 10-30 rpm and a screen hole size of 1-5 mm. ticular infrared absorption bands at 2945, 2812, 1678, 1627,

According to various embodiments ofa third aspect of the 1448, 1377, 1173, 960 and 779 cm-' on the IR (KBr) spec-present invention is provided Hydrate A defined according to trum.

one or more of the embodiments described herein wherein so According to another embodiment ofthe fourth aspect ofsaid Hydrate is made by a process as described herein, the present invention is provided aripiprazole drug substance

According to a fourth aspect of the present invention is of low hygroscopicity wherein said drug substance has an

provided aripiprazole drug substance of low hygroscopicity. 11-1-NMiR spectrum which is substantially the same as the

According to a first embodiment ofthe fourth aspect ofthe 111-INIMR spectrum (DMSO-d6, TMS) shown in FIG. 4.

present invention is provided aripiprazole drug substance of 65 According to another embodiment ofthe fourth aspect oflow hygroscopicity wherein said low hygroscopicity is a the present invention is provided aripiprazole drug substancemoisture content of0.5% or less after placing said drug sub- of low hygroscopicity wherein said drug substance has an


7

Case 1:16-

US 9,359,302 B2

'11-NMR spectrum (DMSO-d6, TMS) having characteristic Anhydrous Aripiprazole Crystals B wherein said processpeaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), comprises heating Aripiprazole Hydrate A.2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMS0), 2.78 According to a first embodiment of the fifth aspect of theppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 Present invention is provided a process for the preparation ofppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm 5 Anhydrous Aripiprazole Ciystals B wherein said process(dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H), comprises heating Aripiprazole Hydrate A at 90-125° C. for7.11-7.17 ppm (n, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 about 3-50 hours.ppm (s, 1H). According to another embodiment ofthe fifth aspect ofthe

present invention is provided a process for the preparation ofAccording to another embodiment of the fourth aspect ofio Anhydrous Aripiprazole Crystals B wherein said processthe present invention is provided aripiprazole drug substance

prim ses heating Aripi razole Hydrate A at 100° C. forof low hygoscopicity wherein said drug substance exhibits caboout 18 hoursP

an endothennic peak near about 141.5° C. in thermogravi- According to another embodiment ofthe fifth aspect ofthemetric/differential thermal analysis (heating rate 5° C./min). present invention is provided a process for the preparation ofAccording to another embodiment of the fourth aspect ofis Anhydrous Aripiprazole Crystals B wherein said processthe present invention is provided aripiprazole drug substance comprises heating Aripiprazole Hydrate A at 100° C. forof low hygroscopicity wherein said drug substance exhibits about 24 hours.

an endothermic peak near about 140.7° C. in differential According to another embodiment ofthe fifth aspect ofthescanning calorimetry (heating rate 5° Cumin), present invention is provided a process for the preparation ofAccording to another embodiment of the fourth aspect of 20 Anhydrous Aripiprazole Crystals B wherein said processthe present invention is provided aripiprazole drug substance comprises heating Aripiprazole Hydrate A at 120° C. forof low hygroscopicity wherein said drug substance is Anhy- about 3 hours.drous Aripiprazole Crystals B and will not substantially con- According to another embodiment ofthe fifth aspect ofthevert to a hydrous form ofaripiprazole when properly stored present invention is provided a process for the preparation ofeven for an extended period. For instance, said Anhydrous 25 Anhydrous Aripiprazole Crystals B wherein said processAripiprazole Crystals B can be stored under a relative humid- comprises heating Aripiprazole HydrateA for about 18 hoursity (RH) of 60% and at a temperature of 25° C., even for a at 100° C. followed by additional heating for about 3 hours atperiod not less than 1 year. 120° C.

According to another embodiment of the fourth aspect of According to a sixth aspect of the present invention isthe present invention is provided aripiprazole drug substance 30 providedAnhydrous Aripiprazole Crystals B defined accord-of low hygroscopicity wherein said drug substance is Anhy- ing to one or more ofthe embodiments described herein anddrous Aripiprazole Crystals B and will not substantially con- made by a process as provided herein.vert to a hydrous form ofaripiprazole when properly stored According to a seventh aspect of the present invention iseven for an extended period. For instance, said Anhydrous providedAnhydrous Aripiprazole Crystals B formulated withAripiprazole Crystals B canbe stored under a relative humid- 35 one or more pharmaceutically acceptable carriers.ity (RH) of 60% and at a temperature of 25° C., even for a Other embodiments ofthe present invention may compriseperiod not less than 4 years. suitable combinations of two or more of the embodimentsAccording to another embodiment of the fourth aspect of and/or aspects disclosed herein.the present invention is provided aripiprazole drug substance Yet other embodiments andaspects ofthe invention will beof low hygroscopicity wherein said drug substance is Anhy- ao apparent according to the description provided below.drous Aripiprazole Crystals B and will not substantially con- Yet another aspect ofthe present invention comprised dis-vert to a hydrous form ofaripiprazole when properly stored covering that when aripiprazole hydrate (Conventionaleven for a period not less than 0.5 year under a relative Hydrate as defined herein) is milled, it converts to an arip-humidity (RH) of75% and at a temperature of40° C. iprazole hydrate (Hydrate A as defined herein) with a differ-According to another embodiment of the fourth aspect of 45 ent powder x-ray diffraction spectrum by different peakthe present invention is provided aripiprazole drug substance intensities. Moreover, it was found that Hydrate A loses theof low hygroscopicity wherein said drug substance has a sharp dehydrationendothermic peak of123.5° C. which char-mean size of50 pm or less when small particle size is required acterizes iinmilled Conventional Hydrate in thermogravimet-for the formulation such as Tablet and other solid dose for- ric/differential thermal analysis. Thus, the Conventionalmulations including for example flashmelt formulations. so Hydrate is transformed into Hydrate A after milling Conven-According to another embodiment of the fourth aspect of tional Hydrate and exhibits a gradual dehydration endother-the present invention is provided aripiprazole drug substance mic peak between about 60° C. and 120° C. with a weak peakof low hygroscopicity wherein said drug substance has a at about 71° C.mean size of40 pm or less ifsmall particle size is required for Yet another aspect ofthe invention comprised discoveringthe formulation such as Tablet and other solid dose formula- 55 that when heated to a specific temperature of 90-125° C. fortions including for example flashmelt formulations. 3-50 hr, this novel aripiprazole hydrate dehydrates graduallyAccording to another embodiment of the fourth aspect of avoiding the aggregation phenomenon thought to be causedthe present invention is provided aripiprazole drug substance in conventional aripiprazole hydrate by rapid dehydration,of low hygroscopicity wherein said drug substance has a and that anhydrous aripiprazole crystals obtained by heatingmean size of30 pm or less ifsmall particle size is required for 60 ofthe novel aripiprazole hydrate to a specific temperature areformulation such as Tablet and other solid dose formulations anhydrous aripiprazole crystals with the desired properties.including for example flashmelt formulations. Characterization of Hydrate A

According to a fifth aspect ofthe present invention is pro- Particles of "HydrateA" as used herein have the physico-vided a process for the preparation ofAnhydrous Aripipra- chemical properties given in (1)-(5) below:zole Crystals B. 65 (1) It has an endothermic curve which is substantially the

According to a first embodiment of the fifth aspect of the same as the thermogravimetric/differential thermal analysispresent invention is provided a process for the preparation of (heating rate 5° C./min) endothetroic curve shown in FIG. 1.

Copy provided by USPTO from the PIRS Image Database on owlcoma

cv-05400- 13^1013^11Case 1:16-

US 9,359,302 B2

9 10Specifically, it is characterized by the appearance of a small as long as they are methods commonly used for measuringthepeak at about 71° C. and a gradual endothermic peak around water content ofcrystals. For example, a method such as the60° C. to 120° C. Karl Fischer method can be used.

(2) It has an 11-1-NMR spectrum which is substantially the (12) When the small particle size is required for the formu-same as the 1H-NMR spectrum (DMSO-d6, TMS) shown in 5 lation such as tablet and other solid dose formulations includ-FIG. 2. Specifically, it has characteristic peaks at 1.55-1.63 ing for example flashmelt formulations, the mean particlesizeppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), is preferably 50 pm or less.2.48-2.56 ppm (m, 4H~DMS0), 2.78 ppm (t, J=7.4 Hz, 2H), Process for Manufacturing Anhydrous Aripiprazole Crystals2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), B6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 to In case ofthe formulation for which small particle size (lessHz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), than 50 pm) is required, the milling is necessary for the7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 111). preparation. However, when a large amount of Conventional

(3) It has a powder x-ray diffraction spectrum which is Anhydrous Aripiprazole orAnhydrous Aripiprazole Crystalssubstantially the same as the powder x-ray diffraction spec- B having large particle size is milled, the milled substancestrum shown in FIG. 3. Specifically, it has characteristic peaks 15 adhere with each other in the milling machine. Accordingly,at 20=12.6°, 15.4°, 17.30, 18.0°, 18.6°, 22.5° and 24.8°. there is a disadvantage that it is difficult to industriallyprepare(4) It has clear infrared absorption bands at 2951, 2822, Anhydrous Aripiprazole Crystals B having small particle1692, 1577, 1447, 1378, 1187, 963 and 784 cm-1 on the IR size.(KBr) spectrum. Under the circumstances, the inventors of the present(5) It has a mean particle size of 50 pm or less. 20 inventionhave found that Conventional hydrate can be easilyProcess for Manufacturing Hydrate A milled, and Anhydrous Aripiprazole Crystals B having small

Hydrate A is manufactured by milling Conventional particle size can be obtained in high yield with good-oper-Hydrate. Conventional milling methods can be used to mill ability by heating the milled hydrate A thus obtained.Conventional Hydrate. For example, Conventional Hydrate The Anhydrous Aripiprazole Crystals B of the presentcan be milled in a milling machine. A widely used milling 25 invention are prepared for example by heating the aforemen-machine can be used, such as an atomizer, pin mill, jet mill or tionedAripiprazole HydrateA at 90-125° C. Theheating timeball mill. Of these, the atomizer is preferred. is generally about 3-50 hours, but cannot be stated uncondi-

Regarding the specific milling conditions when using an tionally since it differs depending on heating temperature.atomizer, a rotational speed of5000-15000 rpm could be used The heating time and heating temperature are inverselyfor the main axis, for example, with a feed rotation of 10-30 30 related, so that for example the heating time will be longertherpm and a screen hole size of 1-5 mm. lower the heating temperature, and shorter the higher the

The mean particle size of the Aripiprazole Hydrate A heating temperature. Specifically, if the heating temperatureobtained by milling should normally be 50 pm or less, pref- ofAripiprazole HydrateA is WO° C., the heating time shoulderably 30 pm or less. Mean particle size can be ascertained by normally be 18 hours or more orpreferably about 24 hours. Ifthe particle size measurement method described hereinafter. 35 the heating temperature ofAripiprazoleHydrate A is 120° C.,Characterization ofAnhydrous Aripiprazole Crystals B on the other hand, the heating time can be about 3 hours. The

"Anhydrous Aripiprazole Crystals B" ofthe present inven- Anhydrous Aripiprazole Crystals B of the present inventiontion as usedherein have the physicochemical properties given can be prepared with certainty by heating Aripiprazolein (6)-(12) below. Hydrate A for about 18 hours at 100° C., and then heating it

(6) They have an 11-1-NMR spectrum which is substantially 40 for about 3 hours at 120° C. The Anhydrous Aripiprazolethe same as the 11-1-NIAR spectrum (DMSO-c16, TMS) shown Crystals B ofthe present invention can also be obtained ifthein FIG. 4. Specifically, they have characteristic peaks at 1.55- heating time is extended still further, but this may not be1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, economical.4H), 2.48-2.56 ppm (m, 4H+DMS0), 2.78 ppm (t, J=7.4 Hz, When small particle size is not required for the formula-2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 45 tion, e.g., when drug substance is being manufactured for2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, injectable ororal solution formulations, Anhydrous Aripipra-J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm zole Crystal B can be also obtained the following process.(m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s; 1H). The inventors also discovered that it is possible to obtain

(7) They have a powderx-ray diffraction spectrum which is anhydrous aripiprazole crystals by heating conventional arip-substantially the same as the powder x-ray diffraction spec- so iprazolehydrate or conventionalanhydrous aripiprazole crys-trum shown in FIG. 5. Specifically, they have characteristic tals to a specific temperature but this process does not yieldpeaks at 20=11.0°, 16.6°, 19.3°, 20.3° and 22.1°. Anhydrous Aripiprazole Crystal B crystalline substance suit-(8) They have clear infrared absorption bands at 2945, able for commercial use in the formulation of solid oral dose

2812, 1678, 1627, 1448, 1377, 1173, 960 and 779 cm-1 onthe formulations.IR (KBr) spectrum. 55 Furthermore, the Anhydrous Aripiprazole Crystals B ofthe

(9) They exhibit an endothermic peak near about 141.5° C. present invention are prepared for example by heating con-in thennogravimetric/differential thermal analysis (heating ventional anhydrous aripiprazole crystals at 90-125° C. Therate 5° C./min). heating time is generally about 3-50 hours, but cannot be

(10) They exhibit an endothermic peak near about 140.7° stated unconditionally since it differs depending on heatingC. in differential scanning calorimetry (heating rate 5° 60 temperature. The heating time and heating temperature areC./min). inversely related, so that for example the heating time will be

(11) Anhydrous Aripiprazole Crystals B of the present longer the lower the heating temperature, and shorter theinvention have low hygroscopicity. For example, Anhydrous higher the heating temperature.Aripiprazole Crystals B of the present invention maintain a Specifically, if the heating temperature of the anhydrouswater content of0.4% or less after 24 hours inside a dessicator 65 aripiprazole crystals is 100° C., the heating time can be aboutset at a temperature of 60° C. and a humidity of 100%. 4 hours, and ifthe heating temperature is 120° C. the heatingWell-known methods ofmeasuring water content can be used time can be about 3 hours.


Case 1:16-cv-05400-JB

US 9,359,302 B211 12

In addition toAripiprazole HydrateA andAnhydrousArip- 5. The present invention relates a process for preparingiprazole Crystals B mentioned above, the present invention anhydrous aripiprazole crystals stated in the aforementionedprovidesAnhydrous Aripiprazole Crystals C to G as follows. item 1, characterized by heating anhydrous aripiprazole crys-

1. The present invention relates to anhydrous aripiprazole tals at a temperature being higher than 140° C. and lower thancrystals (hereinafter referred to as "type C crystals of anhy- 5 150° C.drous aripiprazole") having the following physicochemical 6. The present invention relates a process for preparingproperties (1) to (5): anhydrous aripiprazole crystals stated in the aforementioned

(1) an endothermic curve which is substantially identical to item 2, characterized by recrystallizing from toluene.the thermogravimetric/differential thermal analysis (heating 7. The present invention relates to a process for preparingrate: 5° C./min.) endothermic curve shown in FIG. 8;

to anhydrous aripiprazole crystals stated in the aforementioned(2) an '11-NMR spectrum which is substantially identical item 3, characterized by heating and dissolving anhydrous

to the 1H-NMR spectrum (DMSO-d5, TMS) shown in FIG. 9; aripiprazole crystals in acetonitrile, and cooling it.(3) a powder X-ray diffraction spectrum which is substan- 8. The present invention relates to a process for preparing

tially identical to the powder X-ray diffraction spectrum is anhydrous aripiprazole crystals stated in the aforementionedshown in FIG. 10; item 4, characterized by heating a suspension of anhydrous

(4) an IR spectrum which is substantially identical to the IR aripiprazole crystals in acetone.

(KBr) shown in FIG. 11; and 9. The present invention relates to a pharmaceutical com-

(5) a solid '3C-N1VIR spectrum which is substantially iden- position containing at least one anhydrous aripiprazole crys-tical to the solid "C-NMR spectrum shown in FIG. 12. 20 tals selected from the group consisting ofthe anhydrous arip-

2. The present invention relates to anhydrous aripiprazole iprazole crystals stated in the aforementioned item 1, thecrystals (hereinafter referred to as "type D crystals ofanhy- anhydrous aripiprazole crystals stated in the aforementioneddrous aripiprazole") having the following physicochemical item 2, the anhydrous aripiprazole crystals stated inthe afore-properties (6) to (10): mentioned item 3, the anhydrous aripiprazole crystals stated

(6) an endothermic curvewhich is substantially identical to 25 in the aforementioned item 4, and the anhydrous aripiprazolethe thermogravimetric/differential thermal analysis (heating crystals stated in the after-mentioned item 10, together withrate: 5° C./min.) endothermic curve shown in FIG. 13; pharmaceutically acceptable carriers.

(7) an 114-NMR spectrum which is substantially identical 10. Thepresent invention relates to anhydrous aripiprazoleto the 1E-NMR. spectrum (DMS0-45, TMS) shown in FIG. crystals (hereinafter referred to as "type G crystals ofanhy-14; 30 drous aripiprazole") having the following physicochemical

(8) a powder X-ray diffraction spectrum which is substan- properties (19) to (22):tially identical to the powder X-ray diffraction spectrum (19) an endothermic curve which is substantially identicalshown in FIG. 15; to the thermogravimetric/differential thermal analysis (heat-

(9) an IR spectrum which is substantially identical to the IR ing rate; 5° C./min.) endothermic curve shown FIG. 26.(KBr) shown in FIG. 16; and 35 (20) an'H-NMR spectrum which is substantially identical

(10) a solid 13C-NMR spectrum which is substantially to the 1E-NMR spectrum (DMSO-d,, TMS) shown in FIG.identical to the 13C-NMR spectrum shown in FIG. 17. 27.

3. The present invention relates to anhydrous aripiprazole (21) a power X-ray diffraction spectrum which is substan-crystals (hereinafter referred to as "type E crystals of anhy- tially identical to the powerX-ray diffraction spectrumshowndrous aripiprazole") having the following physicochemical ao in FIG. 28; andproperties (11) to (14): (22) an IR spectrum which is substantially identical to the

(11) an endothermic curve which is substantially identical IR (Kbr) shown in FIG. 29.to the thermogravimetric/differential thermal analysis (heat- 11. The present invention relates to a process for preparinging rate: 5° C./min.) endothermic curve shown in FIG. 18; anhydrous aripiprazole crystals stated in the aforementioned

(12) an '11-NMR spectrum which is substantially identical 45 item 10, characterized by putting glassy state ofAnhydrousto the '1-1-NMR spectrum (DMS0-4, TMS) shown in FIG. Aripiprazole in a sealed vessel and keeping it at room tem-

19; perature for at least 2 weeks.(13) a powderX-ray diffraction spectrum which is substan- 12. Thepresent invention relates to a process for the prepa-

tially identical to the powder X-ray diffraction spectrum ration of granules, characterized by wet granulating conven-

shown in FIG. 20; and 50 tional Anhydrous Aripiprazole Crystals or Anhydrous Arip-(14) an IR spectrum which is substantially identical to the iprazole Crystals B, C, D, E, F or G, drying the obtained

IR (KBr) shown in FIG. 21. granules at 70 to 100° C. and sizing it, then drying the sized4. The present invention relates to anhydrous aripiprazole granules at 70 to 100° C. again.

crystals (hereinafter referred to as "type F crystals of anhy- 13. The present invention relates to a process for the phar-drous aripiprazole") having the following physicochemical ss maceutical solid oral preparation, characterized by drying a

properties (15) to (18): pharmaceutical solid oral preparation comprising conven-

(15) an endothennic curve which is substantially identical tional Anhydrous Aripiprazole Crystals or Anhydrous Arip-to the thermogravimetric/differential thermal analysis (heat- iprazole Crystals B, C, D, E, F or G, and one or more phar-ing rate: 5° C./min.) endothermic curve shown in FIG. 22; maceutically acceptable carriers at 70 to 100° C.

(16) an 111-NMR spectrum which is substantially identical 60 14. The present invention relates to a pharmaceutical solidto the 111-NMR spectrum (DMS0-4, TMS) shown in FIG. oral preparation comprising Anhydrous Aripiprazole Crys-23; tals B, C, D, E, F or G and one or more pharmaceutically

(17) a powderX-ray diffiaction spectrum which is substan- acceptable carriers, wherein said pharmaceutical solid oraltially identical to the powder X-ray diffraction spectrum preparation has at least one dissolution rate selectedfrom theshown in FIG. 24; and 65 group consisting 60% or more at pH 4.5 after 30 minutes,

(18) an IR spectrum which is substantially identical to the 70% or more at pH 4.5 after 60 minutes, and 55% or more atIR (KBr) shown in FIG. 25. pH 5.0 after 60 minutes.

Copy provided by USPTO from the PIPS Image Database on 08/10/2016

08/10/2016

Case 1:16-cv-05400-JBS-KMW-Document 1-3 Fi

US 9,359,302 B213 14

15. The present invention relates to a pharmaceutical solid ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43oral preparation having at least one dissolution rate selected ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz,from the group consisting 60% or more at pH 4.5 after 30 1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H),minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H);more at pH 5.0 after 60 minutes. 5 (3) a powder X-ray diffraction spectrum which is substan-

16. The present invention relates to a pharmaceutical solid tially identical to the powder X-ray diffiaction spectrumoral preparation obtained by wet granulating conventional shown in FIG. 10. Specifically, it has characteristic peaks atAnhydrous Aripiprazole Crystals, drying the obtained gran- 20=12.6°, 13.7°, 15.4°, 18.1°, 19.00, 20.6°, 23.5° and 26.4°;ules at 70 to 100° C. and sizing it, then dtying the sized (4) an IR spectrum which is substantially identical to the IRgranules at 70 to 100° C. again, and the pharmaceutical solid to (KBr) spectrum shown in FIG. 11. Specifically, it has clearoral preparationhas at least one dissolutionrate selected from

inf ed absorption bands at 2939, 2804, 1680, 1375 and 780the group consisting 60% or more at pH 4.5 after 30 minutes, -1.70% or more at pH 4.5 after 60 minutes, and 55% or more at cmand

(5) a solid 13C-NMR spectrum which is substantially iden-pH 5.0 after 60 minutes.17. The present invention relates to a pharmaceutical solid 15

tical to the solid 13C-NIVIR spectrum shown in FIG. 12, spe-oral preparation obtained by drying a pharmaceutical solid cifically, it has characteristic peaks at 32.8 ppm, 60.8 ppm,oral preparation comprising conventional Anhydrous Arip- 74.9 ppm, 104.9 ppm, 152.2 ppm, 159.9 ppm and 175.2 ppm.iprazole Crystals and one or more pharmaceutically accept- Preparation Method ofType C Crystals ofAnhydrous Arip-able carriers at 70 to 100° C., and the pharmaceutical solid iprazoleoral preparation has at least one dissolution rate selected from 20 Type C crystals of anhydrous aripiprazole of the presentthe group consisting 60% or more at pH 4.5 after 30 minutes, invention is prepared, for example by heating an anhydrous70% or more at pH 4.5 after 60 minutes, and 55% or more at aripiprazole at a temperature ofhigher than 140° C. and lowerpH 5.0 after 60 minutes. than 150° C.

18. The present invention relates to a process for the prepa- Anhydrous aripiprazole used as the raw material may beration of granules, characterized by wet granulating conven- 25 conventional anhydrous aripiprazole crystals, for example,tional Aripiprazole Hydrate Crystals, drying the obtained type-I crystals of anhydrous aripiprazole, type-II crystals ofgranules at 70 to 100° C. and sizing it, then drying the sized anhydrous aripiprazole crystals and the like, and these anhy-granules at 70 to 100° C. again. drous aripiprazoles may be either purified products or crude

19. The present invention relates to a process for the phar- materials. Alternatively, type B crystals of anhydrous arip-maceutical solid oral preparation, characterized by drying a 30 iprazole, type D crystals of anhydrous aripiprazole, type Epharmaceutical solid oral preparation comprising conven- crystals of anhydrous aripiprazole, type F crystals of anhy-tional Aripiprazole Hydrate Crystals and one or more phar- drous aripiprazole, or type G crystals ofanhydrous aripipra-maceutically acceptable carriers at 70 to 100° C. zole being prepared inthe present invention canbeused as the

20. The present invention relates to a pharmaceutical solid raw material of anhydrous aripiprazole. These anhydrousoral preparation obtained by wet granulating conventional 35 aripiprazoles can be used singly or in combination ofat leastAripiprazole Hydrate Crystals, drying the obtained granules 2 kinds thereof.at 70 to 100° C. and sizing it, then drying the sized granules at Heating temperature is generally higher than 140° C. and70 to 100° C. again, and the pharmaceutical solid oral prepa- lower than 150° C., preferably at 142-148° C., and heatingration has at least one dissolution rate selected from the group time is generally for 15 minutes to 3 hours, preferably for 30consisting 60% or more at pH 4.5 after 30 minutes, 70% or ao minutes to 1 hour.more at pH 4.5 after 60 minutes, and 55% or more at pH 5.0 When, an anhydrous aripiprazole is heated at the above-after 60 minutes. mentioned temperature, then type C crystals of anhydrous

21. The present invention relates to a pharmaceutical solid aripiprazole are formed.oral preparation obtained by drying a pharmaceutical solid Thus obtained type C crystals of anhydrous aripiprazoleoral preparation comprising conventional Aripiprazole 45 can be isolated and purified by well-known methods. ForHydrate Crystals and one or more pharmaceutically accept- example, after heating the anhydrous aripiprazole at theable carriers at 70 to 100° C., and the pharmaceutical solid above-mentionedtemperature, andby cooling to a room tem-oral preparation has at least one dissolutionrate selected from perature, then type Ccrystals ofanhydrous aripiprazole, hav-the group consisting 60% or more at pH 4.5 after 30 minutes, ing 100% ofpurity can be obtained.70% or more at pH 4.5 after 60 minutes, and 55% or more at so Type D Crystals ofAnhydrous AripiprazolepH 5.0 after 60 minutes. Type D crystals of anhydrous aripiprazole of the present

The Type C to F crystals of anhydrous aripiprazole of the invention have the following physicochemical properties (6)present invention correspond to the Type-III to VI crystals of to (10):anhydrous aripiprazole disclosed in JP-2001-348276. (6) an endothermic curve whichis substantially identical toType C Crystals ofAnhydrous Aripiprazole 55 the thennogravimetric/differential thermal analysis (heating

Type C crystals of anhydrous aripiprazole of the present rate: 5° C./min.) endothermic curve shown in FIG. 13; more

invention have the following physicochemical properties (1) particularly, it has an endothermic peak around 136.8° C. andto (5): 141.6° C.;

(1) an endothermic curve which is substantially identical to (7) an 111-NMR spectrum which is substantially identicalthe thermogravimetric/differential thermal analysis (heating 60 to the 1H-NMR spectrum (DMSO-d6, TMS) shown in FIG.rate: 5° C./min.) endothermic curve shown in FIG. 8, more 14. Specifically, it has characteristic peaks at 1.55-1.63 ppmparticularly, it has an endothermic peak around 150.2° C.; (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H),

(2) an 111-NMR spectrum which is substantially identical 2.48-2.56 ppm (m, 4H+DMS0), 2.78 ppm (t, J=7, 4 Hz, 2H),to the 1H-NMR spectrum (DMSO-d,, TMS) shown inFIG. 9. 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H),Specifically, it has characteristic peaks at 1.55-1.63 ppm (m, 65 6.43 ppm (d, J=2.4 Hz, 111), 6.49 ppm (dd, J=8.4 Hz, J=2.42H), 1.68-1.78 ppm (m, 211), 2.35-2.46 ppm (m, 411), 2.48- Hz, 111), 7.04 ppm (d, J=8.1 Hz, 111), 7.11-7.17 ppm (m, 1H),2.56 ppm (m, 4H+DMS0), 2.78 ppm (t, J=7, 4 Hz, 211), 2.97 7.28-7.32 ppm (m, 211) and 10.00 ppm (s, 1H);


Case 1:16-cv-05400-JBS-KMW Document 1-3 Fi

US 9,359,302 B215 16

(8) a powder X-ray diffraction spectrum which is substan- (14) an IR spectrum which is substantially identical to thetially identical to the powder X-ray diffraction spectrum IR (KBr) spectrum shown in FIG. 21. Specifically, ithas clearshown in FIG. 15. Specifically, it has characteristic peaks at infrared absorption bands at 2943, 2817, 1686, 1377, 1202,20=8.7°, 11.6°, 16.3°, 17.7°, 18.6°, 20.3°, 23.4° and 25.0°; 969 and 774 crn-'.

(9) an IR spectrum which is substantially identical to the IR 5 Preparation Method ofType E Crystals ofAnhydrous Arip-(KBr) spectrum shown in FIG. 16. Specifically, it has clear iprazoleinfrared absorption bands at 2946, 1681, 1375, 1273, 1175 Type E crystals of anhydrous aripiprazole of the presentand 862 cm-1; and invention is prepared, for example by recrystallization of the

(10) a solid "C-NMR spectrum which is substantially anhydrous aripiprazole from acetonitaile. Specifically, byidentical to the solid "C-NMR spectrum shown in FIG. 17, to adding a well-known anhydrous aripiprazole to acetonitrile,specifically, it has characteristic peaks at 32.1 ppm, 62.2 ppm, heating and dissolving, then the solution thus obtained may66.6 ppm, 104.1 ppm, 152.4 ppm, 158.4 ppm, and 174.1 ppm. be cooled. In accordance with such procedures, type E crys-Preparation Method ofType D Crystals ofAnhydrous Arip- tals of anhydrous aripiprazole of the present invention are

iprazole separated out in the acetonitrile.Type D crystals of anhydrous aripiprazole of the present 15 When a conventional anhydrous aripiprazole is added to

invention is prepared, for example, by recrystallization of acetonitrile, type-I crystals ofanhydrous aripiprazole, type-IIanhydrous aripiprazole from toluene. Specifically, an anhy- crystals of anhydrous aripiprazole and type D crystals ofdrous aripiprazole is added to toluene, further heated and anhydrous aripiprazole are separated out, other than type Edissolved, then thus obtained solution is cooled. By such crystals ofanhydrous aripiprazole. Plate crystals being sepa-procedures, type D crystals ofanhydrous aripiprazole of the 20 rated out from the acetonitrile solution at 70° C. are type-Ipresent invention is separated out as crystals in toluene. crystals, type-II crystals and type D crystals, while type E

Anhydrous aripiprazole to be used as the raw materials crystals are precipitated out as needle crystals. When themay be conventional anhydrous aripiprazole, for example acetonitrile solution after separated out of these crystals istype-I crystals of anhydrous aripiprazole, type-II crystals of heated again (for example, heated at over 75° C.), the plateanhydrous aripiprazole and the like, and these anhydrous 25 crystals (type-I crystals, type-II crystals and type D crystals)aripiprazoles may be either purified products or crude mate- are quickly dissolved, on the contrary, the needle form crys-rials.Altematively, type B crystals ofanhydrous aripiprazole, tals (type E crystals) do not dissolved. Additionally, when thetype C crystals of anhydrous aripiprazole, type E crystals of acetonitrile solution iscooled again, thenneedle formcrystalsanhydrous aripiprazole, type F crystals ofanhydrous aripipra- (type E crystals) are further separated out around the needlezole, or type G crystals of anhydrous aripiprazole being pre- 30 form crystals (type E crystals) previously precipitated as thepared in the present invention can be used as the raw material seed crystals. Thus, type E crystals ofanhydrous aripiprazolefor anhydrous aripiprazoles. These anhydrous aripiprazoles can be precipitated in the acetonitrile solution.can be used singly or in combination of at least 2 kinds Anhydrous aripiprazoles used as the raw materials may bethereof. conventional anhydrous aripiprazoles, for example any one of

When the solution obtained by heating and dissolving is 35 type-I crystals ofanhydrous aripiprazole and type-II crystalscooled, type D crystals of anhydrous aripiprazole may be ofanhydrous aripiprazole and the like, and these anhydrousadded as a seed crystal to said solution. Further, the seed aripiprazoles may be either purified products or crude mate-

crystal may be formed by cooling gradually said solution rials. Alternatively, type B crystals ofanhydrous aripiprazole,being obtained by heating and dissolving. In the presence of type C crystals ofanhydrous aripiprazole, type D crystals ofthe seed crystal, type D crystals of anhydrous aripiprazole ao anhydrous aripiprazole, type F crystals ofanhydrous aripipra-may be separated out. zole, or type G crystals ofanhydrous aripiprazole canbe used

Thus separated out type D crystals of anhydrous aripipra- as the raw materials for anhydrous aripiprazoles.These anhy-zole can be isolated and purified in accordance with well- drous aripiprazoles can be used singly or incombination ofatknown methods. By such procedures, type D crystals ofanhy- least 2 kinds thereof.drous aripiprazole, having the purity of 100% can be 45 When the acetonitrile solution obtained by heating (heat-obtained. ing and dissolving) is cooled, the type E crystals ofaripipra-Type E Crystals ofAnhydrous Aripiprazole zole may be added as a seed crystal to said solution. Further,

Type E crystals of anhydrous aripiprazole of the present the seed crystal may be formed by cooling gradually saidinventionhave the following physicochemical properties (11) acetonitrile solution which was obtained by heating.to (14): so Thus separated out type E crystals of anhydrous aripipra-

(11) an endothermic curve which is substantially identical zole can be isolated and purified in accordance with well-to the thermogravimetric/differential thermal analysis (heat- known methods. By suchprocedures, type E crystals ofanhy-ing rate: 5° C./min.) endothermic curve shown in FIG. 18, drous aripiprazole, having the purity of 100% can bespecifically, it has an endothermic peak around 146.5° C.; obtained.

(12) an 'H-NMR spectrum which is substantially identical 55 Type F Crystals ofAnhydrous Aripiprazoleto the 'H-NMR spectrum (DMSO-d,, TMS) shown in FIG. Type F crystals of anhydrous aripiprazole of the present19. Specifically, it has characteristic peaks at 1.55-1.63 ppm inventionhave the followingphysicochemical properties (15)(m, 211), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), to (18):2.48-2.56 ppm (m, 4H+DMS0), 2.78 ppm (t, J=7, 4 Hz, 2H), (15) an endothermic curve which is substantially identical2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 60 to the thermogravimetric/differential thermal analysis (heat-6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 ing rate: 5° C./min.) endothennic curve shown in FIG. 22,Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), specifically, ithas anendothermic peaks around 137.5° C. and7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H); 149.8° C.;

(13) a powder X-ray diffraction spectrum which is substan- (16) an 1H4IVIR spectrum which is substantially identicaltially identical to the powder X-ray diffraction spectrum 65 to the 11-1-NMR spectrum (DMSO-d6, TMS) shown in FIG.shown in FIG. 20. Specifically, it has characteristic peaks at 23. Specifically, it has characteristic peaks at 1.55-1.63 ppm20=8.0°, 13.7°, 14.6°, 17.6°, 22.5° and 24.0'; and (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H),


Copy provided by USPTO 08/10/2016


US 9,359,302 B217 18

2.48-2.56 ppm (m, 4H+DMS0), 2.78 ppm (t, J=7, 4 Hz, 2H), (22) an IR spectrum which is substantially identical to the2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), IR (KBr) spectrum shown in FIG. 29. Specifically, ithas clear6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 infrared absorption bands at 2942, 2813, 1670, 1625, 1377,Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 1195, 962 and 787 cm-1.7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H); 5 Preparation Method ofType G Crystals ofAnhydrous Arip-

(17) a powder X-ray diffraction spectrum which is substan- iprazoletially identical to the powder X-ray diffraction spectrum Type G crystals of anhydrous aripiprazole of the presentshown in FIG. 24. Specifically, it has characteristic peaks at invention canbe prepared, forexampleby putting glassy state

28=11.3°, 13.3°, 15.4°, 22.8°, 25.2° and 26.9°, and of anhydrous aripiprazole in a sealed vessel and leaving to

to stand itat room temperature forat leasttwo weeks, preferably(18) Having an IR spectrum which is substantially identi-two weeks to six months. Further, glassy state of anhydrouscal to the IR (KBr) spectrum shown in FIG. 25. Specifically, aripiprazole as starting material can be obtained by heatingit has clear infrared absorption bands at 2940, 2815, 1679, and melting anhydrous anprprazole at around 170° C., then

1383, 1273, 1177, 1035, 963 and 790 cm-1. cooling it to room temperature.Preparation Method ofType F Crystals ofAnhydrous Arip- is Anhydrous aripiprazole used as the raw material may beiprazole well-known anhydrous aripiprazole crystals, for example,

Type F crystals of anhydrous aripiprazole of the present any one oftype-I crystals ofanhydrous aripiprazole and type-invention is prepared, for example by suspending an anhy- H crystals of anhydrous aripiprazole and the like, and thesedrous aripiprazole in acetone, and thus obtained acetone sus- anhydrous aripiprazoles may be either purified products or

pension is heated. zo crude materials. Alternatively, type B crystals of anhydrousAnhydrous aripiprazoles used as the raw materials may be aripiprazole, type C crystals of anhydrous aripiprazole, type

conventional anhydrous aripiprazole, for example any one of D crystals ofanhydrous aripiprazole, type E crystals ofanhy-type-I crystals ofanhydrous aripiprazole and type-II crystals drous aripiprazole, or type F crystals of anhydrous aripipra-of anhydrous aripiprazole and the like, and these anhydrous zolebeing prepared inthepresent invention can be used as the

aripiprazoles may be either purified products or crude mate- 25 raw material of anhydrous aripiprazoles. These anhydrousrials.Alternatively, type B crystals ofanhydrous aripiprazole, aripiprazoles can be used singly or incombination ofat least

type C crystals ofanhydrous aripiprazole, type D crystals of 2 kinds thereof.

anhydrous aripiprazole, type E crystals of anhydrous arip- Thus obtained type G crystals of anhydrous aripiprazolecan be isolated and purified by well-known methods. Foriprazole, or type G crystals of anhydrous aripiprazole pre-

30 example, glassy state ofanhydrous aripiprazole leave to standpared in thepresent invention canbe used as the raw materialsaccording to the above-mentioned method, then type G crys-for anhydrous aripiprazoles. These anhydrous aripiprazoles

can be used singly or in combination of at least 2 kindstals of anhydrous aripiprazole, having 100% ofpurity can beobtained.

thereof. Type C crystals ofanhydrous aripiprazole, type D crystalsHeating temperature of the acetone suspension may be

35 ofanhydrous aripiprazole, type E crystals ofanhydrous arip-generally about the boiling point ofacetone, and heating time iprazole, type F crystals ofanhydrous aripiprazole and typeGis generally 5 to 10 hours. When the acetone suspension is crystals of anhydrous aripiprazole of the present inventionheated about the boiling point ofacetone, then type F crystals neither easily convert into hydrates thereof, nor substantiallyof anhydrous aripiprazole is fonned, the crystals are isolated decrease the original solubility, even whenthey are stored forby filtration with heating. Isolation of the crystals may be 40 a long period of time.carried out in accordance with well-known methods. By such In accordance with the present invention, methods for pre-procedures, type F crystals ofanhydrous aripiprazole, having paring anhydrous aripiprazole crystals having high purity,the purity of 100% can be obtained, which can apply in an industrial scale with a good repeatabil-Type G Crystals ofAnhydrous Aripiprazole ity is provided.

Type G crystals of anhydrous aripiprazole of the present 45 In accordance with the present invention, pharmaceuticalinventionhave the following physicochemical properties (19) compositions comprising anhydrous aripiprazole crystals are

to (22): provided, of which the solubility does not decrease, and of

(19) an endothermic curve which is substantially identical which the stability can keep excellent, even if they are storedto the thermogravimetric/differential thermal analysis (heat- for long time.ing rate: 5° C./min.) endothermic curve shown in FIG. 26, so The anhydrous aripiprazole crystals which are the raw

more particularly, it has an endothermic peak around 141.0° material for preparing theAnhydrous Aripiprazole Crystals BC. and an exothermic peak around 122.7° C.; to G of the present invention are prepared for example by

(20) an 1H-NMR spectrum which is substantially identical Method a or b below.to the 1H-NMR spectrum (DMS0-(16, TMS) shown in FIG. "Method a": Process for Preparing Crude Aripiprazole Crys-27. Specifically, it has characteristic peaks at 1.55-1.63 ppm 55 tals

(m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), Conventional Anhydrous Aripiprazole crystals are pre-2.48-2.56 ppm (m, 4H+DMS0), 2.78 ppm (t, J=7.4 Hz, 2H), pared by well-known methods, as described in Example 1 of2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 211), Japanese Unexamined Patent Publication No. 191256/1990.6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 A suspension of 47 g of 7-(4-bromobutoxy)-3,4-dihydro-Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 111), 7.04 ppm (d, 60 carbostyril, 35 g ofsodium iodide with 600 ml ofacetonitrileJ=8.1 Hz, 1H), 7.11-7.17 ppm (m, 111), 7.28-7.32 ppm (m, was refluxed for 30 minutes. To this suspension was added 40

2H) and 10.00 ppm (s, 1H); g of 1-(2,3-dichlorophenyl)piperazine and 33 ml of triethy-(21) a powder X-ray diffraction spectrum which is substan- lamine and the whole mixture was further refluxed for 3

tially identical to the powder X-ray diffraction spectrum hours. After the solvent was removed by evaporation, theshown in FIG. 28. Specifically, it has characteristic peaks at 65 residue thus obtained was dissolved in chloroform, washed

28=10.1°, 12.8°, 15.2°, 17.0°, 17.5°, 19.1°, 20.1°, 21.2°, withwater thendried withanhydrous magnesium sulfate. The

22.4°, 23.3°, 24.5° and 25.8'; and solvent was removed by evaporation, and the residue thus

from the II1 Image umanase on

Case 1:16-cv-05400-JBS=KMW--Ducument 1-3

US 9,359,302 B219 20

obtained was recrystallized from ethanol twice, to yield 57.1 and other disintegration inhibitors; quaternary ammoniumg of 7-1444-(2,3-dichloropheny1)-1-piperazinyl]butoxyl -3, salt, sodium lauryl sulfate and other absorption promoters;4-dihydrocarbostyril. glycerine, starch and other moisture retainers; starch, lactose,

Colorless flake crystals kaolin, bentonite, colloidal silic acid and other adsorbents;Melting point 139.0-139.5° C. 5 and refined talc, stearate, boric acid powder, polyethylene

"Method b": Process for Preparing Conventional Anhydmus glycol and other lubricants and the like. Tablets can also beAripiprazole formulated if necessary as tablets with ordinary coatings,

The Method b is described in the Proceedings of the 4th such as sugar-coated tablets, gelatin-coated tablets, entericJapanese-Korean Symposium on Separation Technology coatedtablets and film coated tablets, as well as double tablets(Oct. 6-8, 1996). to and multilayered tablets.

Furthermore, the AnhydrousAripiprazole Crystals B ofthe When a pill formulation is used, a wide variety of carrierspresent invention are prepared for example by heating con- that are known in the field can be used. Examples includeventional aripiprazole hydrate at 90-125° C. The heating time glucose, lactose, starch, cacao butter, hardened vegetable oil,is generally about 3-50 hours, but cannot be stated uncondi- kaolin, talc and otherexcipients; gum arabic powder, traganthtionally since it differs depending on heating temperature. 15 powder, gelatin, ethanol and other binders; and laminaran,The heating time and heating temperature are inversely agar and other disintegrators and the like.related, so that for example the heating time will be longer the When a suppository formulation is used, a wide variety oflower the heating temperature, and shorter the higher the carriers that are known in the field can be used. Examplesheating temperature. Specifically, if the heating temperature include polyethylene glycol, cacao butter, higher alcohol,of the aripiprazole hydrate is 100° C., the heating time can be 20 esters ofhigher alcohol, gelatin semi-synthetic glyceride andabout 24 hours, while if the heating temperature is 120° C., the like.the heating time can be about 3 hours. Capsules are prepared according to ordinary methods by

The aripiprazole hydrate which is the raw material for mixing anhydrous aripiprazole crystals with the various car-

preparing the Anhydrous Aripiprazole Crystals B of the riers described above and packing them in hard gelatin cap-present invention is prepared for example by Method c below. 25 stiles, soft capsules, hydroxypropylmethyl cellulose capsules"Method c": Process for Preparing Conventional Hydrate (HPMC capsules) and the like.

Aripiprazole hydrate is easily obtained by dissolving the In addition, colorants, preservatives, perfumes, flavorings,anhydrous aripiprazole crystals obtained by Method a above sweeteners and the like as well as otherdrugs maybe includedin a hydrous solvent, and heating and then cooling the result- in the medicinal composition.ing solution. Using this method, aripiprazole hydrate is pre- 30 In case of forming the pharmaceutical solid oral prepara-cipitated as crystals in the hydrous solvent. tion in the form ofgranules, it can be prepared by wet granu-

An organic solvent containing water is usually used as the lating a mixed powder ofgranulating ingredients comprising,hydrous solvent. The organic solvent should be one which is anhydrous aripiprazole crystals (conventional anhydrousmiscible with water, such as for example an alcohol such as aripiprazole crystals or anhydrous aripiprazole crystalsmethanol, ethanol, propanol or isopropanol, a ketone such as 35 selected from the group consisting ofanhydrous aripiprazoleacetone, an ether such as tetrahydrofuran, dimethylforma- type B, C, D, E, F and G crystals) and various carriers whichmide, or a mixture thereof, with ethanol being particularly are heretofore well-known in this field, such as excipients,desirable. The amount ofwater in the hydrous solvent can be disintegrators, disintegration inhibitors, humectants, absorp-10-25% by volume of the solvent, or preferably close to 20% tion accelerators, adsorbents, lubricants, colorants and theby volume. 40 like (for the examples of these agents, those of previouslyMedicinal Composition mentioned can be referred to) by adding a liquid (generally,

Amedicinal composition ofthe present invention will con- water or an aqueous solution containing binding agents). AstainAnhydrous Aripiprazole Crystals B, C, D, E, F and G in for the wet granulation, there are various methods are

a pharmaceutically acceptable carrier or combination ofcar- included, for example, fluidized bed granulation, kneadingriers. 45 granulation, extruding granulation, rotating granulation and

Carriers which are pharmaceutically acceptable include the like can be mentioned. Among these methods, in case ofdiluents and excipients generally used in pharmaceuticals, conducting the fluidized bed granulation, the granulatingsuch as fillers, extenders, binders, moisturizers, disintegra- ingredients containing various carriers are mixed with inlettors, surfactants, and lubricants, air, then upon continued fluidizing the granulating ingredi-

The medicinal composition ofthe present invention maybe 50 ents and the liquid is sprayed to conduct ganulation. In case

formulated as anordinarymedicinal preparation, for example of conducting the kneading granulation, the granulatingin the form of tablets, flashmelt tablets, pills, powder, liquid, ingredients containing various carriers are mixed by agita-suspension, emulsion, granules, capsules, suppositories or as tion, then upon continued agitating the granulating ingredi-an injection (liquid, suspension, etc.). ents, granulation is conducted by adding the liquid. After the

When a tablet formulation is used, a wide variety ofcarriers 55 granulation, if necessary, the obtained granules are sized to

that are known in the field can be used. Examples include make them to the desired size by use of a suitable sieve or a

lactose, saccharose, sodium chloride, glucose, xylitol, man- mill having suitable screen size. The granules thus obtainednitol, erythritol, sorbitol, urea, starch, calcium carbonate, by such a method are dried again in addition to usual dryingkaolin, crystal cellulose, silic acid and otherexcipients; water, being conducted when preparing the granules. As for the

ethanol, propanol, simple syrup, glucose liquid, starch liquid, 60 drying methods, various methods can be applied, forgelatin solution, carboxymethyl cellulose, shellac, methyl example, methods by use ofa fluidized bed dryer, a fan dryer,cellulose, potassium phosphate, polyvinyl pyrolidone and a vacuum dryer and the like can be mentioned. Generally,other binders; dried starch, sodium alginate, agar powder, drying methods can be conducted under conventional condi-laminaran powder, sodium bicarbonate, calcium carbonate, tions, for example, in case of using the fluidized bed dryer,polyoxyethylene sorbitan fatty acid esters, sodium lauryl sul- 65 drying procedure is conducted with an air flow of0.5 m3/minfate, monoglyceride stearate, starch, lactose and other disin- to 50 m3/min, an inlet air temperature at 70 to 100° C. for 10

tegrators; saccharose, stearin, cacao butter, hydrogenated oil min to 1 hour. After dried, the granules are subjected to size,


•-i is ent 1-3 Filed-09t02t1-6 Page 57 of 89 PagelD: 69

US 9,359,302 B2

21 22then further dried. In case ofusing the fluidized bed dryer or istration should contain in the range of about 1-100 mg of

fan dryer or the like, the drying procedure is conducted under Anhydrous Aripiprazole Crystals B, more particularly 1-30

the conditions with an air flow of0.5 nDmin to 50 m3/min, an mg per unit dose.

inlet air temperature at 70 to 100° C. for 1 to 6 hours. In case The medicinal composition of the present invention is

ofusing the vacuum dryer, the drying procedure is conducted 5 extremely stable, with substantially no decrease in solubilityunder the conditions ofreduced pressure ofabout at 0-10 torr even when stored for long periods oftime.

ofdegree ofvacuum at 70 to 100° C. ofjacket temperature for The medicinal composition of the present invention is

1 to 6 hour.effective in the prevention and treatment of central nervous

system disorders such as schizophrenia and may also beThe thus prepared granules may be used as they are for the

to effective in the treatment of intractable (drug-resistant,pharmaceutical solid oral preparations, or if necessary, they chronic) schizophrenia with cognitive impairment and intrac-may be shaped in the form of tablets. Further, the dried

table (drug-resistant, chronic) schizophrenia without cogni-granules dried by usual manner are shaped in the form of.nye iincludin•mpairment, anxiety g mild anxiety, mania

tablets, then they may be dried again. includingbipolar disorder acute mania and acute mania, bipo-

The thus prepared pharmaceutical solid oral preparation is lar disorder, depression including bipolar disorder depres-comprising anhydrous aripiprazole crystals hardly changes to sion, autism, Down's syndrome, attention deficit hyperactiv-hydrates even if they are stored for a long period of time, ity disorder (ADHD), Alzheimer's disease, Parkinson'stherefore the pharmaceutical solid oral preparation, ofwhich disease and other neurodegenerative diseases, panic, obses-

dissolution rate does not hardly lowered (dissolution rate to sive compulsive disorder (OCD), sleep disorders, sexual dys-maintain maximum drug concentration (Cmax): 60% or 20 function, alcohol and drug dependency, vomiting, motion

higher dissolution rate obtained after 30 minutes at pH 4.5, sickness, obesity, miparticlee headache and cognitive impair-70% orhigher dissolutionrate obtained after 60 minutes at pH ment.

4.5, or 55% or higher dissolution rate obtained after 60 min- Analytical Methods

utes at pH 5.0) can be provided. (1) The 1H-NMR spectrum was measured in DMSO-d6Another pharmaceutical solid oral preparation can be pro- 25 using TMS as the standard.

vided by granulating a conventional aripiprazole hydrate (2) Powder X-ray Diffraction

crystals by a method similar to that ofmentioned above, and Using a Rigaku Denki RAD-2B diffractionmeter, thepow-

dried by usual manner under similar conditions, then dried der x-ray diffraction pattern was measured at room tempera-

again. Alternatively, the dried granules dried by usual mannerture using a Cu Ka filled tube (35 kV 20 mA) as the x-ray

30 source with a wide-angle goniometer, a 10 scattering slit, an

are shaped to tablets form, then they are dried again, then0.15 mm fight-intercepting slit, a graphite secondary mono-

pharmaceutical solid oral preparations of which dissolutionchromator and a scintillation counter. Data collection was

rate does not lowered (dissolution rate to maintain maximum done in 20 contm.nous scan mode at a scan speedof5°/minutedrug concentration (Cmax): 60% or higher dissolution rate.

m scan steps of 0.02° in the range of3° to 40°.obtained after30 minutes atpH 4.5, 70% orhigherdissolution

35 (3) The IR spectrum was measured by the KBr method.rate obtained after 60 minutes at pH 4.5 or 55% or higher (4) Thermogravimetric/Differential Thermal Analysisdissolution rate obtained after 60 minutes at pH 5.0) can be Thermogravimetric/differential thermal analysis was per-provided. These facts can be understood that, the conven- formed using a Seiko SSC 5200 control unit and a TG/DTAtional anhydrous aripiprazole crystals or the aripiprazole 220 simultaneous differential thermal/thermogravimetrichydrate crystals contained in the pharmaceutical solid oral 40 measurement unit. 5-10 mg samples were placed in open

preparation are changed to "B type crystals" of anhydrous aluminum pans and heated from 20° C. to 200° C. in a dryaripiprazole by drying twice, nitrogen atmosphere at a heating rate of5° C./minute. a-alu-

The amount ofAnhydrous Aripiprazole Crystals B, C, D, mina was used as the standard substance.

E, F and G that should be included in the medicinal compo- (5) Differential Scanning Calorimetrysition of the present invention can be selected from a wide 45 Thermogravimetric/differential thermal analysis was per-

range suitable for the indication sought to be treated. Gener- formed using a Seiko SSC 5200 control unit and a DSC 22° C.

ally, the Anhydrous Aripiprazole Crystals B should be present differential scanning calorimeter. 5-10 mg samples were

in about 1-70% by weight or particularly about 1-30% by placed in crimped aluminum pans and heated from 20° C. to

weight based on the medicinal composition. 200° C. in a dry nitrogen atmosphere at a heating rate of5°

The method of administration of the medicinal composi- so C./minute. a-alumina was used as the standard substance.

tion of the present invention may be adjusted to suit, for (6) Particle Size Measurement

example, the formulation ofthe drug product, the age, gender 0.1 g ofthe particles to be measured were suspended in a 20

and other conditions (including the severity thereof) of the ml n-hexane solution of 0.5 g soy lecithin, and particle size

patient. In the case of tablets, pills, liquids, suspensions, was measured using a size distribution meter (Microtrackemulsions, granules and capsules, for example, administra- 55 HRA, Microtrack Co.).tion is oral. In the case of an injection, it is administered (7) Hygroscopicity Test Method

intravenously either by itself or mixed with an ordinary One g ofthe sample was accurately weighed ina weighingreplenisher such as glucose or amino acids, or may also be bottle (diameter 5 cm), covered with kimwipes and left to rest

administered by itselfintramuscularly, intracutaneously, sub- in a 60° C./100% RH environment (water/dessicator). 24

cutaneously or intraperitoneally, as necessary. In the case ofa 60 hours later, the weighing bottle was removed, transferred to

suppository, administration is intrarectal. an environment of a room temperature and about 30% RH

The dosage of the medicinal composition of the present (magnesium chloride hexahydrate saturated water solution/

invention is selected depending on the usage, the age, gender dessicator) and left to rest for 24 horns and the water content

and other conditions of the patient, the severity ofthe condi- of the sample was measured by the Karl Fischer method.

tion and so forth, but ordinarily the amount of anhydrous 65 (8) Solid '3C-NMR Spectrometryaripiprazole crystals can be about 0.1-10 mg per 1 kg ofbody Solid 13C-NMR spectrum was measured under the condi-

weight per day. The preparation which is the unit ofadmin- tions as follows.


cv-05400-J-BS=Kiv1W—Document 1-3 Filed O9IO2it Pctye 58 of89 PagelD. 70Case 1:16-

US 9,359,302 B223 24

Measuring apparatus: CMX-360 Solid State NMR Spec- When left for 24 hours in a dessicator set at humiditytrometer (manufactured by Chemagnetic Inc.) 100%, temperature 60° C., these crystals exhibited hygro-

Computer: SPARC Station 2 (manufactured by SUN scopicity of 1.78% (see Table 1 below).Microsystem, Inc.)

OS, Software: Solalis 1.1.1 Rev. B (Registered trademark: S Reference Example 3

UNIX), Spinsight Ver. 2.5Name of measured pulse: TOSS method (TOSS is a pro- 820 g of the intermediate wet-state aripiprazole hydrate

gram name of the apparatus) among CP/MAS method. obtained in Reference Example 2 was dried for 2 hours at 50°Width of measured puls: 90° puls was used under the C. to obtain 780 g of aripiprazole hydrate crystals. These

condition ofCP. 10 crystals had a moisture value of3.82% according to the KarlMeasuring sample tube: Test tube made ofzirconia, having Fischer method. As shown in FIG. 6, thermogravimetric/

the outside diameter of7.5 mm, and inside capacity of0.8 ml differential thermal analysis revealed endothermic peaks atRevolution: 4250 Hz (Revolution per second Contact time: 75.0, 123.5 and 140.5° C. Because dehydration began near

1 msec. 70° C., there was no clear melting point (mp).Waiting time: 20 sec. 15As shown in FIG. 7, the powder x-ray diffraction spectrumIntegrated times: 512 times of aripiprazole hydrate obtained by this method exhibitedMeasuring temperature: About 25° C. temperature of out-

characteristic peaks at 213=12.6°, 15.10, 17.4°, 18.2°, 18.7°,side of test tube) 24.8° and 27.5°.External standard: Methyl group (8 17.3) of hexamethyl-benzene was used as the external standard. 20 The powder x-ray diffraction spectrum of this aripiprazole

The present invention is explained in more detail below hydrate was identical to the powder x-ray diffraction spec-

using reference examples, examples, sample preparations trum of aripiprazole hydrate presented at the 4th Joint Japa-and formulation examples. nese-Korean Symposium on Isolation Technology.

Reference Example 1 25 Reference Example 4

19.4 g of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril and Preparation of 15 mg tablets containing type I crystals of16.2 g of 1-(2,3-dichlorophenyl) piperadine 1 hydrochloride anhydrous aripiprazole obtained in Reference Example 2.were added to 8.39 g ofpotassium carbonate dissolved in 140 Type-I crystals ofanhydrous aripiprazole (525 g), lactoseml ofwater, and circulated for 3 hours under agitation. After 30 (1,995 g), corn starch (350 g) andcrystalline cellulose (350 g)reaction the mixture was cooled and the precipitated crystals were charged in a fluidized bed granulating dryer (Flowfiltered out. These crystals were dissolved in 350 ml of ethyl coater FLO-5, manufactured by FREUND INDUSTRIALacetate, and about 210 ml of water/ethyl acetate azeotrope CO., LTD.), and these granulating ingredients were mixed byremoved under reflux. The remaining solution was cooled, fluidizing for about 3 minutes with an inlet air temperature atand the precipitated crystals filtered out. The resulting crys- 35 70° C. and air flow rate of3 m3/min. Further, the granulatingtals were dried for 14 hours at 60° C. to produce 20.4 g ingredients were upon continued fluidizing under the same(74.2%) of raw aripiprazole. condition and sprayed about 1,400 g of the aqueous solution

30 g ofthe raw aripiprazole obtained above was recrystal- to obtained wet granules. The wet granules were dried underlized from 450 ml of ethanol according to the methods inlet air at temperature at 80° C., for about 15 minutes. Thedescribed in Japanese Unexamined Patent Publication No. 40

obtained dried granules contained 4.3% of water. (Yield:191256/1990, and the resulting crystals dried for 40 hours at99%). The dried ules were subjected to sizing by passing80° C. to obtain anhydrous aripiprazole crystals. The yield

was 29.4 (98.0%). to a sieve of 710 um.The melting point (mp) of these anhydrous aripiprazole About 1% by weight ofmagnesium stearate was added to

crystals was 140° C., matching the melting point ofthe anhy- 45 the sized granules and mixed, then the granules were supplieddrous aripiprazole crystals described in Japanese Unexam- to a tablet machine (Rotary single tabletpress 12HUK: manu-

Med Patent Publication No. 191256/1990. factured by KIKUSUI SEISAKUSHO CO., LTD.), thereWhen these crystals were left for 24 hours in a dessicator were obtained tablets, each having 95 mg ofweight.

set at humidity 100%, temperature 60° C., they exhibited Water content of the tablets was measured according to

hygroscopicity of 3.28% (see Table 1 below). so volumetric titration method (Karl-Fischer method) describedin water content measuring method in Japanese Pharmaco-

Reference Example 2 poea or the electrical quantity titration method.Water Content Measuring Method:

6930 g of the intermediate raw aripiprazole obtained in Sample (0.1 to 0.5 g) (incase ofa tablet, 1 tablet was used)Reference Example 1 was heat dissolved in 138 liters of 55 was weighed precisely, and the water content was measuredhydrous ethanol (watercontent 20%) according to the method by use ofa water content measuring equipment.presented at the 4th Japanese-Korean Symposium on Sepa- Volumetric titration:ration Technology, gradually (2-3 hours) cooled to room tem- Automated water content measuring equipmentperature, and then chilled to near 0° C. The precipitated Model: KF-06 (manufacture byMITSUBISHI CHEMI-crystals were filtered out, producing about 7200 g ofaripipra- 60 CAL CORP.)zole hydrate (wet state). Electrical Quantity Titration Method:

The wet-state aripiprazole hydrate crystals obtained above Automated micro-water content measuring equipmentwere dried for 30 hours at 80° C. to obtain 6480 g (93.5%) of Model: AQ-7F (manufactured by HIRANUMAconventional anhydrous aripiprazole crystals. The melting SANGYO CO., LTD.)point (mp) ofthese crystals was 139.5° C. Thesecrystals were 65 Automated water vaporization equipment Model:confirmed by the Karl Fischer method to be anhydrous, with LE-20S (manufactured by HIRANUMA SANGYOa moisture value of0.03%. CO., LTD.)


5

US 9,359,302 B225 26

Heating temperature: 165±10° C. ecule) between 60-120° C.—clearly different fromthe endot-Nitrogen gas flow rate: about 150 ml/min. hermic curve of umnilled aripiprazole hydrate (see FIG. 6).

Reference Example 5 Example 2

Preparation of 15 mg tablets containing type B crystals of 450 g of the Aripiprazole Hydrate A (powder) obtained inanhydrous aripiprazole Example 1 was dried for 24 hours at 100° C. using a hot air

Type B crystals of anhydrous aripiprazole (4,500 g), lac- dryer to produce 427 g (yield 98.7%) ofAnhydrous Aripipra-tose (17, 100 g), cornstarch (3,000 g) and crystalline cellulose zole Crystals B.(3,000 g) were charged in a fluidized bed granulating dryer 10 These Anhydrous Aripiprazole Crystals B had a melting(NEW-MARUMERIZER Model: NQ-500, manufactured by point (mp) of 139.7° C.Fun PAUDAL CO., LTD.), and these granulating ingredients The Anhydrous Aripiprazole Crystals B obtained abovewere mixed by fluidizing for about 3 minutes with an inlet air had an 11I-NMR spectrum (DMSO-c16, TMS) which was sub-

temperature at 70° C., air flow rate of 10 to 15 m3/min.is

stantially the same as the'H-NMR spectrum shown in FIG. 4.Further, the granulating ingredients were upon continued flu- Specifically, they had characteristic peaks at 1.55-1.63 ppmidizing under the same condition, and sprayed about 12,000 g (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H),of 5% aqueous solution of hydroxypropyl cellulose to 2.48-2.56 ppm (m, 4H+DMS0), 2.78 ppm (t, J=7.4 Hz, 2H),obtained wet granules. The wet granules were dried under 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H),inlet air at temperature at 85° C., for about 28 minutes. The 20 6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4thus obtained dried granules contained 3.8% ofwater (mea- Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H),sured by the method according to Reference Example 4). 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).(Yield: 96%). The dried granules were subjected to sizing by The Anhydrous Aripiprazole Crystals B obtained abovepassing to a sieve of 850 gm. had a powder x-ray diffraction spectrum which was substan-

About 1% by weight ofmagnesium stearate was added to 25 tially the same as the powder x-ray diffraction spectrumthe sized granules and mixed, then the granules were supplied shown in FIG. 5. Specifically, they had characteristic peaks atto a tabletmachine (Rotary single tablet press 12HIJK: mama- 20=11.0°, 16.6°, 19.3°, 20.3° and 22.1°.factured by KIKUSUI SEISAKUSHO CO., LTD.), there The Anhydrous Aripiprazole Crystals B obtained abovewere obtained tablets, each having 95 mg ofweight. had remarkable infrared absorption bands at 2945, 2812,

30 1678, 1627, 1448, 1377, 1173, 960 and 779 cm-d on the IRExample 1 (KBr) spectrum.

The Anhydrous Aripiprazole Crystals B obtained above500.3 g of the aripiprazole hydrate crystals obtained in exhibited an endothennic peak near about 141.5° C. in ther-

Reference Example 3 were milled using a sample mill (small mogravimetric/differential thermal analysis.atomizer). The main axis rotation rate was set to 12,000 rpm

35 The Anhydrous Aripiprazole Crystals B obtained aboveand the feedrotation rate to 17 rpm, and a 1.0mmherringbone exhibited an endothermic peak near about 140.7° C. in dif-

screen was used. Milling was completed in 3 minutes, result- ferential scanning calorimetry.ing in 474.6 g (94.9%) ofAripiprazole Hydrate A powder. Even when the Anhydrous Aripiprazole Crystals B

TheAripiprazole Hydrate A (powder) obtained in this wayobtained above were left for 24 hours in a dessicator set at

ao humidity 100%, temperature 60° C., they did not exhibithad a mean particle size of20-25 pm. The melting point (mp) hygroscopicity exceeding 0.4% (See Table 1 below).was undetermined because dehydration was observed begin-ning near 70° C.

Example 3The Aripiprazole Hydrate A (powder) obtained above

exhibited an 11-1-NMR (DMS0-415, TMS) spectrum which as 44.29 kg ofthe Aripiprazole Hydrate A (powder) obtainedwas substantially the same as the 1H-NMR spectrum shown in Example 1 was dry heated for 18 hours in a 100° C. hot airin FIG. 2. Specifically, it had characteristic peaks at 1.55-1.63 dryer and then heated for 3 hours at 120° C. to produce 42.46ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), kg (yield 99.3%) ofAnhydrous Aripiprazole Crystals B.2.48-2.56 ppm (m, 4H+DMS0), 2.78 ppm (t, J=7.4 Hz, 2H), The physicochemical properties of the resulting Anhy-2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), so drous Aripiprazole Crystals B were the same as the physico-6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 chemical properties of the Anhydrous Aripiprazole CrystalsHz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), B obtained in Example 2.7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H). The Anhydrous Aripiprazole Crystals B obtained in this

The Aripiprazole Hydrate A (powder) obtained above bad way did not exhibit hygroscopicity ofmore than 0.4% even

a powder x-ray diffraction spectrum which was substantially 55 when left for 24 hours in a dessicator set at humidity 100%,the same as the powder x-ray diffraction spectrum shown in temperature 60° C. (see Table 1 below).FIG. 3. Specifically, it had characteristic peaks at 20=12.6°,15.4°, 17.3°, 18.0°, 18.6°, 22.5° and 24.8°. This pattern is Example 4different from the powder x-ray spectrum of unmilled arip-iprazole hydrate shown in FIG. 7. so 40.67 kg ofthe Aripiprazole Hydrate A (powder) obtained

The Aripiprazole Hydrate A (powder) obtained above had in Example 1 was dry heated for 18 hours in a WO° C. hot airinfrared absorption bands at 2951, 2822, 1692, 1577, 1447, dryer and then heated for 3 hours at 120° C. to produce 38.951378, 1187, 963 and 784 cm-i on the IR (KBr) spectrum. kg (yield 99.6%) ofAnhydrous Aripiprazole Crystals B.

As shown in FIG. 1, the Aripiprazole Hydrate A (powder) The physicochemical properties of the resulting Anhy-obtained above had a weak peak at 71.3° C. in thermogravi- 65 drous Aripiprazole Crystals B were the same as the physico-metric/differential thermal analysis and a broad endothermic chemical properties of the Anhydrous Aripiprazole Crystalspeak (weight loss observed corresponding to one water mol- B obtained in Example 2.


KMW uocurnent 1-3 Filed uutuziro rage bU of riu ragelu. tz

Copy provided

Case 1:16-cv-05400-JBS-

US 9,359,302 B227 28

The Anhydrous Aripiprazole Crystals B obtained in this same as the physicochemical properties of the Anhydrousway did not exhibit hygroscopicity ofmore than 0.4% even Aripiprazole Crystals B obtained in Example 2.when left for 24 hours in a dessicator set at humidity 100%, The Anhydrous Aripiprazole Crystals B obtained in thistemperature 60° C. (see Table 1 below), way did not exhibit hygroscopicity of more than 0.4% even

Examples 5-10 are useful for injectable or oral solution 5 when left for 24 hours in a dessicator set at humidity 100%,formulations but not solid dose formulations since they were temperature 60° C. (see Table 1 below).made by heating Conventional Anhydrous Aripiprazole or

Conventional Hydrate instead ofHydrate A. Example 10

Example 5 to The aripiprazole hydrate crystals obtained in ReferenceExample 3 were heated for 3 hours at 120° C. using the same

The hygroscopic anhydrous aripiprazole crystals obtained methods as in Example 2. The physicochemical properties ofin Reference Example 1 were heated for 50 hours at 100° C. the resulting Anhydrous Aripiprazole Crystals B were the

using the same methods as in Example 2. The physicochemi- same as the physicochemical properties of the Anhydrous15cal properties of the resulting Anhydrous Aripiprazole Crys-Aripiprazole Crystals B obtained in Example 2.

tals B were the same as the physicochemical properties ofthe The Anhydrous Aripiprazole Crystals B obtained in this

Anhydrous Aripiprazole Crystals B obtained in Example 2. way exhibited hygroscopicity of no more than 0.4% even

The Anhydrous Aripiprazole Crystals B obtained in this when left for 24 hours in a dessicator set at humidity 100%,way did not exhibit hygroscopicity ofmore than 0.4% even temperature 60° C. (see Table 1 below).when left for 24 hours in a dessicator set at humidity 100%, 20

temperature 60° C. (see Table 1 below). Example 11

Example 6 Preparation ofType C Crystals ofAnhydrousAripiprazole

The hygroscopic anhydrous aripiprazole crystals obtained 25

in Reference Example 1 were heated for 3 hours at 120° C. 100 Milligrams of type-I crystals of anhydrous aripipra-using the same methods as in Example 2. The physicochemi- zole obtained in Reference Example 2 were heated aboutcal properties of the resulting Anhydrous Aripiprazole Crys- 145° C. (±3° C.). In this occasion, there was observed thetals B were the same as the physicochemical properties ofthe phenomena that the crystals were once melted, then againAnhydrous Aripiprazole Crystals B obtained in Example 2. 30 crystallized. Alter that, 100 mg (yield: 100%) of Type C

The Anhydrous Aripiprazole Crystals B obtained in this crystals of anhydrous aripiprazole were obtained. The melt-

way did not exhibit hygroscopicity of more than 0.4% even ing point of the crystals was 150° C. The crystals were col-when left for 24 hours in a dessicator set at humidity 100%, orless prism form.

temperature 60° C. (see Table 1 below). The type C crystals of anhydrous aripiprazole obtained35 above had an endothermic curve which was substantially

Example 7 identical to the endothermic curve of thermogravimetric/dif-ferential thermal analysis (heating rate: 5° C./minute) shown

The hygroscopic anhydrous atiniprazole crYstals obtained in FIG. 8. Specifically, it showed the endothermic curve

in Reference Example 2 were heated for 50 hours at 100° C. around 150.2° C.

using the same methods as in Example 2. The physicochemi- 40 The type C crystals of anhydrous aripiprazole thuscal properties of the resulting Anhydrous Aripiprazole Crys- obtained exhibited an 1H-NMR spectrum (DMS0-4 TMS)tals B were the same as the physicochemical properties ofthe which was substantially identical to the 11I-NMR spectrumAnhydrous Aripiprazole Crystals B obtained in Example 2. (DMSO-d6, TMS) shown in FIG. 9. Specifically, it had the

The Anhydrous Aripiprazole Crystals B obtained in this characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppmway did not exhibit hygroscopicity ofmore than 0.4% even 45 (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m,when left for 24 hours in a dessicator set at humidity 100%, 4H+DMS0), 2.78ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6

temperature 60° C. (see Table 1 below). Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz,1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d,

Example 8 J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m,so 2H), and 10.00 ppm (s, 1H).

The hygroscopic anhydrous aripiprazole crystals obtained The type C crystals of anhydrous aripiprazole obtainedin Reference Example 2 were heated for 3 hours at 120° C. above had a powder X-ray diffraction spectrum which was

using the same methods as in Example 2. The physicochemi- substantially identical to the powder X-ray diffraction spec-cal properties of the resulting Anhydrous Aripiprazole Crys- trum shown in FIG. 10. Specifically, it had the characteristictals B were the same as the physicochemical properties ofthe 55 peaks at 20=12.6°, 13.7°, 15.4°, 18.1°, 19.00, 20.6°, 23.5° and

Anhydrous Aripiprazole Crystals B obtained in Example 2. 26.4°.The Anhydrous Aripiprazole Crystals B obtained in this The type C crystals of anhydrous aripiprazole obtained

way did not exhibit hygroscopicity ofmore than 0.4% even above had an IR spectrum which was substantially identicalwhen left for 24 hours in a dessicator set at humidity 100%, to the IR (KBr) spectrum shown in FIG. 11. Specifically, it

temperature 60° C. (see Table 1 below). 60 had the characteristic infrared absorption bands at 2939,2804, 1680, 1375 and 780 cm-1.

Example 9 The type C crystals of anhydrous aripiprazole obtainedabove exhibited a solid 13C-NIvIR spectrum, which was sub-

The aripiprazole hydrate crystals obtained in Reference stantially identical to the solid 13C-NMR spectrum shown inExample 3 were heated for 50 hours at 100° C. using the same 65 FIG. 12. Specifically, it had the characteristic peaks at 32.8methods as in Example 2. The physicochemical properties of ppm, 60.8 ppm, 74.9 ppm, 104.9 ppm, 152.2 ppm, 159.9 ppmthe resulting Anhydrous Aripiprazole Crystals B were the and 175.2 ppm.

by USPTO from the PIRS Image Database on 08/1012016

Copy provided by USPTO 08/10/2016

Case 1:16-cv-05400-JBS-KNAW—Document 1-3 Filed -09-102t16--Page 61 of 89 PagelD: 73

US 9,359,302 B229 30

According to the above-mentioned data on endothermic perature 60° C., the crystals did not have hygroscopicitycurve of thermogravimetric/differential thermal analysis higher than 0.4% (see, Table 1 below).(heating rate: 5° C./minute) and powder X-ray diffi-action

spectrum, the formation of the type C crystals of anhydrous Example 13

aripiprazole was confirmed. 5Preparation ofType D Crystals ofAnhydrousWhen the type C crystals of anhydrous aripiprazole crys- Aripiprazoletals obtained above were left for 24 hours in a dessicator

where the conditions 'were set at humidity 100%, and tem- 1,200 Grams of the type-I crystals of anhydrous aripipra-perature 60° C., then the crystals did not exhibit hygroscop- zole obtained in Reference Example 2 were dissolved in 18icity higher than 0.4% (see, Table 1 below). to liters of toluene, with heating. This toluene solution was

cooled to 40° C., and 36 g of type-D crystals of anhydrousExample 12 aripiprazole obtained in Example 12 were added as seed

crystals, thenthe solution was cooled to 10° C. and allowed to

Preparation ofType D Crystals ofAnhydrous stand as it is. The precipitated crystals were collected byAripiprazole ts filtration, dried at 60° C. for 18 hours to obtain 1,073 g (yield:

86.8%) of type D crystals of anhydrous aripiprazole (purity:100%). The crystals were colorless plate form.

The type-I crystals of anhydrous aripiprazole obtained in The type D crystals of anhydrous aripiprazole had anReference Example 2 were added in 200 ml of toluene, and endothermic curve substantially identical to the endothermicdissolved by heating at 74° C. After confirmed that it was 20 curve of thermogravimetric/differential thermal analysisdissolved completely, the toluene solution was cooled to 7° (heating rate: 5° C./minute) shown inFIG. 13. Specifically, itC., and the precipitated crystals were collected by filtration. had the endothermic peaks around about 136.8° C. and aboutThe crystals were subjected to air-drying as they were so as to 141.6°.obtain 17.9 g (yield: 89.5%) of type D crystals ofanhydrous The type D crystals of anhydrous aripiprazole obtained

aripiprazole. 25above exhibited an 11-1-NMR spectrum (DMSO-d,, TMS)which was substantially identical to the 11-1-NMR spectrumThe type D crystals of anhydrous aripiprazole obtained(DMSO-d5, TMS) shown in FIG. 14. Specifically, it had theabove had an endothermic c e substantially identical to thecharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppmendothennic curve ofthermogravimetric/differential thermal(m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m,analysis (heating rate: 5° C./minute) shown in FIG. 13. Spe- 4H+DMS0), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6

cifically, it had the endothermic peaks at about 136.8° C. and 30 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz,about 141.6°. 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d,The type D crystals of anhydrous aripiprazole obtained J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m,above exhibited H-NMR spectrum (DMSO-d,, TMS) which 2H), and 10.00 ppm (s, 1H).was substantially identical to the 11-1-NMR spectrum The type D crystals of anhydrous aripiprazole obtained(DMSO-d6, TMS) shown in FIG. 14. Specifically, they had 35 above had a powder X-ray diffraction spectrum which wasthe characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 substantially identical to the powder X-ray diffraction spec-ppm (m, 211), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, trum shown in FIG. 15. Specifically, it had the characteristic4H~DMS0), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 peaks at 20=8.7°, 11.6°, 16.3°, 17.7°, 18.6°, 20.3°, 23.4° andHz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 25.0°.

1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, 40 The type D crystals of anhydrous aripiprazole obtainedJ=8.1 Hz, 1H), 7.11-7.17 ppm (in, 1H), 7.28-7.32 ppm (m, above had an IR spectrum which was substantially identical

2H), and 10.00 ppm (s, 1H). to the IR (KBr) spectrum shown in FIG. 16. Specifically, it

The type D crystals of anhydrous aripiprazole obtained had characteristic infrared absorption bands at 2946, 1681,above had a powder X-ray diffraction spectrum which was 1375, 1273, 1175 and 862 cm-1.

The type D crystals of anhydrous aripiprazole obtainedsubstantially identical to the powder X-ray diffraction spec- 45above had a solid 13C-NIVIR s ectrum which was substan-trum shown in FIG. 15. Specifically, it had the characteristictially identical to the solid "C-1!3IMR spectrum shown in FIG.

peaks at 20=8.7°, 11.6°, 16.3°, 17.7°, 18.6°, 20.3°, 23.4° and17. Specifically, it had the characteristic peaks at 32.1 ppm,62.2 ppm, 66.6 ppm, 104.1 ppm, 152.4 ppm, 158.5 ppm and

The type D crystals of anhydrous aripiprazole obtained 174.1 ppm.above had an IR spectrum which was substantially identical so According to the above-mentioned data on the endother-to the IR (KBr) spectrum shown in FIG. 16. Specifically, it mic curve of thermogravimetric/differential thermal analysishad the characteristic infrared absorption bands at 2946, (heating rate: 5° C./minute) and powder X-ray diffraction1681, 1375, 1273, 1175 and 862 cm-'. spectrum, the formation of type D crystals of anhydrous

The type D crystals of anhydrous aripiprazole obtained aripiprazole was confmned.above exhibited a solid 13C-NMR spectrum which was sub- 55 When the type D crystals of anhydrous aripiprazole crys-stantially identical to the solid '3C-NMR spectrum shown in tals obtained above were left for 24 hours in a dessicatorFIG. 17. Specifically, it had the characteristic peaks at 32.1 where the conditions were set at humidity 100%, and tern-

Ppm, 62.2 PPm, 66.6 ppm, 104.1 ppm, 152.4 ppm, 158.5 ppm perature 60° C., the crystals did not exhibit hygroscopicityand 174.1 ppm. higher than 0.4% (see, Table 1 below).

According to the above-mentioned data on the endother- 60

mic curve of thermogravimetric/differential thermal analysis Example 14

(heating rate: 5° C./minute) and powder X-ray diffractionspectrum, the formation of type D crystals of anhydrous Preparation ofType E Crystals of Anhydrousaripiprazole was confirmed. Aripiprazole

When the type D crystals ofanhydrous aripiprazole crys- 65

tals obtained above were left for 24 hours in a dessicator 40 Grams of type-I crystals of anhydrous aripiprazolewhere the conditions were set at humidity 100%, and tem- obtained in Reference Example 2 was dissolved in 1000 ml of

from the NIKS image uatanase on

08/10/2016

Case 1:16-cv-05400-JBS-KMW uocument 1-3 Filed 09/02/1b Page 62 of 89 PagelD: 74

US 9,359,302 B231 32

acetonitrile with heating at 80° C. This acetonitrile solution rate: 5° C./minute) shown in FIG. 22. Specifically, it had thewas cooled to about 70° C. by taking for about 10 minutes, exothermic peaks at about 137.5° C. and about 149.8° C.and was kept at this temperature for about 30 minutes to The type F crystals of anhydrous aripiprazole obtainedprecipitate the seed crystals. Next, the temperature of said above exhibited an 111-NMR spectrum (DMSO-d6, TMS)solution was slowly risen to 75° C., and the crystals were 5 which was substantially identical to the 1H-NMR spectrumgrown up by keeping this temperature for 1 hour. Then, the (DMSO-d6, TMS) shown in FIG. 23. Specifically, it had thesolution was cooled to 10° C. by taking about 4 hours, and the characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppmprecipitated crystals were collected by filtration. Thus (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m,obtained crystals were subjected to air-drying overnight, 4H+DMS0), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6there were obtained 37.28 g (yield: 93.2%) of type E crystals I° Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz,ofanhydrous aripiprazole (purity: 100%). The melting point 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d,of these crystals was 145° C., and the crystals were colorless J=8.1 Hz, 1H), 7.11-7.17 ppm (in, 1H), 7.28-7.32 ppm (m,needle form. 2H), and 10.00 ppm (s, 1H).

The type E crystals ofanhydrous aripiprazolehad an endot-15

The type F crystals of anhydrous aripiprazole obtainedhermic curve substantially identical to the endothermic curve above had a powder X-ray diffraction spectrum which was

of thermogravimetric/differential thermal analysis (heating substantially identical to the powder X-ray diffraction spec-rate: 5° C./minute) shown in FIG. 18. Specifically, it had trum shown in FIG. 24. Specifically, it had the characteristicendothermic peak at about 146.5°. peaks at 20=11.3°, 13.3°, 15.4°, 22.8°, 25.2° and 26.9°.

The type E crystals of anhydrous aripiprazole obtained 20 The type F crystals of anhydrous aripiprazole obtainedabove exhibited an '1-1-NMR spectrum (DMSO-d,, TMS) above had an IR spectrum which was substantially identicalwhich was substantially identical to the '1I-NMR spectrum to the IR (KBr) spectrum shown in FIG. 25. Specifically, it(DMSO-d6, TMS) shown in FIG. 19. Specifically, it had the had the characteristic infrared absorption bands at 2940,characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm 2815, 1679, 1383, 1273, 1177, 1035, 963 and 790 cm-1(m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 25 According to the data on endotheimic curve of thermo-4H+DMS0), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 gravimetric/differential thermal analysis (heating rate: 5°Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, C./minute) and powder X-ray diffraction spectrum, the for-1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, mation oftype F crystals of anhydrous aripiprazole was con-J=8.1 Hz, 111), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, firmed.2H), and 10.00 ppm (s, 1H). 30 When the type F crystals ofanhydrous aripiprazolecrystalsThe type E crystals of anhydrous aripiprazole obtained obtained above were left for 24 hours ina dessicatorwhere theabove had a powder X-ray diffraction spectrum which was conditions were set at humidity 100%, and temperature 60°substantially identical to the powder X-ray diffraction spec- C, the crystals did not exhibit hygroscopicity higher thantrum shown in FIG. 20. Specifically, it had the characteristic

0 '4% (see, Table 1 below).peaks at 20=8.0°, 13.7°, 14.6°, 17.6°, 22.5° and 24.0°. 35

The type E crystals of anhydrous aripiprazole obtainedTABLE 1above had an IR spectrum which was substantially identical

to the IR (KBr) spectrum shown in FIG. 21. Specifically, it Initial Moisture Moisture Contenthad the characteristic infrared absorption bands at 2943, Sample Content Alter 24 hrs

2817, 1686, 1377, 1202, 969 and 774 cra'. 40Reference Example 1 0.04 3.28According to the data on the endothermic curve ofthermo- Reference Example 2 0.04 1.78

gravimetric/differential thermal analysis (heating rate: 5° Example 2 0.04 0.04

C./minute) and powder X-ray diffraction spectrum, the for- Example 3 0.02 0.02Example 4 0.02 0.02mation oftype E crystals ofanhydrous aripiprazole was con-Example 5 0.04 0.04firmed. 45Example 6 0.04 0.04

When the type E crystals of anhydrous aripiprazole &ample 7 0.04 0.03obtained above were left for 24 hours ina dessicatorwhere the Example 8 0.04 0.03

conditions were set at humidity 100%, and temperature 60° Example 9 0.03 0.01

Example 10 0.05 0.05C., the crystals did not exhibit hygroscopicity higher than Example 11 0.03 0.030.4% (see, Table 1 below). 50 Example 12 0.04 0.03

Example 13 0.04 0.03

Example 15 Example 14 0.06 0.09Example 15 0.04 0.04

Preparation ofType F Crystals ofAnhydrousAripiprazole 55

Example 16140 Grams of type-I crystals of anhydrous aripiprazole

obtained in Reference Example 2 were suspended in 980 ml a) Type I crystals ofanhydrous aripiprazole (10g) obtained inofacetone and continued to reflux for 7.5 hours with stirring. Reference Example 2 was charged in a stainless steel roundNext, the suspension was filtered in hot condition, and crys- so tray (diameter: 80 mm), and heated to about 170° C. so as totals separated out were subjected to air-drying for 16 hours at melted completely. When this melted liquid was cooled, thenroom temperature, there was obtained 86.19 g (yield: 61.6%) it solidified clarity with pale brawn in color, the solid was

of type F crystals ofanhydrous aripiprazole (purity: 100°/o). peeled off from the stainless steel round tray, there was

The crystals were colorless prism form. obtained 9.8 g (yield: 98%) of glassy state of anhydrousThe type F crystals ofanhydrous aripiprazole had an endot- 65 aripiprazole. The obtained glassy state product was charac-

hermic curve substantially identical to the endothermic curve terized by having no significant peak observed in a powderof thennogravimetric/differential thermal analysis (heating X-ray determination. (cf. FIG. 31).


Copy 08/10/2016

ase 1:16-cv-05400-JBS-KNAW Ducument 1-3

US 9,359,302 B233 34

According to the thermogravimetric/differential thermal obtained dried granules contained 3.6% of water (measuredanalysis (heating rate: 5° C./minute), as shown in FIG. 30, an by the method according to Reference Example 4).exothermic peak oftype B crystals ofanhydrous aripiprazole About 1% by weight ofmagnesium stearate was added to

was observed at around 86.5° C. While, an endothermic peak the sized granules andmixed, then the granules were suppliedto a tabletting machine (a Rotary single tablet press, Modeloftype B crystals ofanhydrous aripiprazole owing to melting 5

was observed at around 140.1° C. VIRGO: manufactured by KIKUSUI SEISAKUSHO CO.,LTD.), and there were obtained tablets, each having 190 mgb) When the glassy state of anhydrous aripiprazole obtained

in Example 16-a) wefe charged in a sealed vessel and left toofweight.c) The dried granules (3 kg) obtained in Example 17-a) werestand at room temperature for about 6 months, then type G charged in a vacuum dryer (vacuum granulating dryermodel;crystals of anhydrous aripiprazole having white in color was 10 VG-50: manufactured by KIKUSUI SEISAKUSHO CO.,obtained by changing the color from pale brown (25 g, yield: LTD.), and dried at 70° C. of a jacket temperature, under a

100%). Melting point: 138 to 139° C. reduced pressure at 5 torr ofdegree ofvacuum for 1 hour. TheThe type G crystals of anhydrous aripiprazole had an thus obtained dried granules contained 3.1% ofwater (mea-

endothermic curve which was substantially identical to the sured by the method according to Reference Example 4). Thethermogravimetric/differential thermal analysis (heating 15 dried granules were subjected to sizing by passing to a sieverate: 5° C./min.) endothermic curve shown in FIG. 26, more of850 um.particularly, it has an endothermic peak around 141.0° C. and About 1% by weight ofmagnesium stearate was added toan exothermic peak around 122.7° C. the sized granules and mixed, then the granules were supplied

The type G crystals of anhydrous aripiprazole obtained as to a tablet machine (Rotary single tablet press, Modelabove exhibited an 11-1-NMR spectrum which was substan- 20 VIRGO: manufactured by KIKUSUI SEISAKUSHO CO.,tially identical to the 1H-NMR spectrum (DMSO-d6, TMS) LTD.), and there were obtained tablets, each having 190 mgshown in FIG. 27. Specifically, it has characteristic peaks at ofweight.1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMS0), 2.78 ppm (t, Example 18

J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, 25a) Preparation of 30 mg tablets containing type B crystals ofJ=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, anhydrous anprprazole1=8.4 Hz, 1=2.4 Hz, 1H), 7.04 ppm (d, 1=8.1 Hz, 1H), 7.11- Anhydrous aripiprazole (type B crystals) (4,500 g), lactose

7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, (17,100 g), corn starch (3,000 g) and crystalline cellulose1H). (3,000 g) were charged in a fluidized bed granulating dryerThe type G crystals of anhydrous aripiprazole obtained as 30 (NEW-MARUMERIZER Model: NQ-500, manufactured byabove had a powder X-ray diffraction spectrum which was FUJI PAUDAL CO., LTD.), andthese granulating ingredientssubstantially identical to the powder X-ray diffraction spec- were mixedby fluidizing for about 3 minutes with an inlet airtrum shown inFIG. 28. Specifically, it has characteristic peak temperature at 70° C., air flow rate of 10-15e/min. Further,at 20=10.1°, 12.8°, 15.2°, 17.0°, 17.5°, 19.1°, 20.1°, 21.2°, the granulating ingredients were continued fluidizing under22.4°, 23.3°, 24.5° and 25.8°. 35 the same condition, and were sprayed with about 12,000 g of

The type G crystals of anhydrous aripiprazole obtained 5% aqueous solution of hydroxypropyl cellulose to obtainabove had an IR spectrum which was substantially identical wet granules. The wet granules were dried under inlet air atto the IR(KBr) spectrum shown in FIG. 29. Specifically, it has temperature of 85° C., for about 30 minutes. The obtainedclear infrared absorption bands at 2942, 2813, 1670, 1625, dried granules contained 3.6% of water (measured by the1377, 1195, 962 and 787 cm-1. 40 method according to Reference Example 4). (Yield: 96%).

The dried granules were sized by passing to a mill (FIOLEExample 17 F-0: manufactured by TOKUJU CORPORATION).

About 1% by weight ofmagnesium stearate was added to

a) Preparation ofgranules of30 mg tablets containing type B the sized granules andmixed, thenthe granules were suppliedcrystals ofanhydrous aripiprazole for additional drying 45 to a tablet machine (a Rotary single tablet press, VIRGO:

Type B crystals of anhydrous aripiprazole (1,500 g), lac- manufactured by KIKUSUI SEISAKUSHO CO., LTD.), andtose (5,700 g), corn starch (1,000 g) and crystalline cellulose there were obtained tablets, each having 190 mg ofweight.(1,000 g) were charged in a fluidized bed granulating dryer b) The tablets (5 kg) obtained in Example 18-a) were charged(Flow Coater Model FLO-5M; manufactured by FROINT in a fan dryer (AQUA COATER AQC-48T, manufactured bySANGYO KABUSHIKI KAISHA), and these granulating so FREUND INDUSTRIAL CO., LTD.), and dried under inletingredients weremixedby fluidizing for about 3 minutes with air at temperature of 90° C., air flow rate of 2 m3/min for 6an inlet air temperature at 60° C., air flow rate of 3 to 4 hours. The obtained dried granules contained 3.3% ofwaterm3/min. Further, the granulating ingredients were continued (measuredby themethod according to Reference Example 4).fluidizing under the same condition, and sprayed with about c) The dried tablets (3 kg) obtained in Example 18-a) were

4,000 g of5% aqueous solution ofhydroxypropyl cellulose to 55 charged in a vacuum dryer (vacuum granulating dryer,obtain wet granules. The wet granules were dried under an VG-50: manufactured by KIKUSUI SEISAKUSHO CO.,inlet air temperature at 85° C., for about 20 minutes. The LTD.), and dried at 80° C. of a jacket temperature, underobtained dried granules contained 3.8% ofwater (measured reduced pressure of 5 torr of degree ofvacuum for 4 hours.by the method according to Reference Example 4). The obtained dried tablets contained 2.7% of water (mea-b) The dried granules (4 kg) obtained in Example 17-a) were 60 sured by the method according to Reference Example 4).sized by use ofa mill (FIORE F-0: manufactured by TOKUJUCORPORATION). Example 19

The sized granules (3 kg) were charged in a fluidized bedgranulating dryer (Flow Coater Model FLO-5M; manufac- a) By the procedures similar to those ofExample 18-a), theretured by FREUND INDUSTRIAL CO., LTD.), and these 65 were obtainedtablets (containing type Icrystals ofanhydrousgranulating ingredients were dried under an inlet airtempera- aripiprazole obtained in Reference Example 2), each havingture at 85° C., and air flow rate of 2 m3/min for 2 hours. The 190 mg ofweight,

provided by USPTO from the PIRS Image Database on

Case 1:16-cv-05400-JBS-KNAW Document 1-3 Filed 09/02116 Page 64 of 89 PagelD: 76

US 9,359,302 B235 36

b) The tablets were dried by the procedures similar to those of by KIKUSUI SEISAKUSHO CO., LTD.), and tableted with

Example 18-b), except that air inlet temperature was 100° C. punch, there were obtained tablets, each having 191 mg of

and dried for 1 hour. weight.c) The tablets were dried by the procedures similar to those of Dissolution Test

Example 18-b), except that inlet air temperature was 100° C. 5 Each tablets of the pharmaceutical solid oral preparationsand dried for 3 hours. obtained previously was kept, respectively underthe open at

25° C./60% RH for 6 months, and at 40° C./75% RH for 1

Example 20 week, then their dissolution rates were measured by the fol-

lowing methods. The dissolution rates obtained from 60 min-

By the procedures similar to those ofExample 18-a), there to utes after the exposure are shown in Tables 2 and 3. Thedissolution rates after 60 minutes, using the tablets kept under

were obtained tablets, each having 190 mg of weightcon-the open at 40° C./75% RH for 2 weeks, are shown in Tables

taining type C crystals of anhydrous aripiprazole., 4 and 5. The dissolution rates after 60 minutes, using the

Example 21 tablets kept under the open condition at 40° C./75% RH for 15 week, are shown in Table 6.

Dissolution test equipment: USPBy the procedures similar to those ofExample 18-a), there

Model: NTR-6100 (manufactured by TOYAMAwere obtained tablets, each having 190 mg of weight, con- SANGYO CO., LTD.)taining type D crystals of anhydrous aripiprazole. Model: DT-610 (manufactured by JASCO CORPORA-

20 TION)Example 22a) Method of Dissolution Test ofthe 15 mg Tablet

One tablet (containing 15 mg each of anhydrous aripipra-a)Aripiprazole hydrate crystals (156 g) obtained in Reference zole or hydrate) was tested by using 900 ml of acetic acidExample 3, lactose (570 g), corn starch (100 g) and crystalline buffer solution (pH 5.0) (Note: 1) as the test solution, and bycellulose (100 g) were charged in a fluidized bed granulating 25 rotating a paddle at 100 rpm according to the method ofUSPdryer (NEW-MARUMERIZER, NQ-160: manufactured by (United States Pharmacopoea) (Note: 2).FUJI POWDAL CO., LTD.), and these granulating ingredi- The test solutions obtained respectively from 10 minutes,ents were mixed under fluidizing for about 3 minutes with an 20 minutes, 30 minutes, 45 minutes and 60 minutes after theinlet air temperature at 60° C., air flow rate of 1.0 to 1.5 start oftest are named as T10, T20, T30, T45 and T60.

m3/min, and rotating disc with rotary speed of 400 rpm. 30 On the other hand, about 0.05 g of standard sample of

Further, the granulating ingredients were continued fluidizing aripiprazole was weighed accurately, dissolved in ethanolunder the same condition, and sprayed about 500 g of 4% (95%) so as to make exactly 50ml ofethanol solution. Twentyaqueous solution of hydroxypropyl cellulose to obtain wet (20) ml of this ethanol solution was taken accurately, and to

granules. The inlet air temperature was elevated up to 85° C., prepared exactly 1000 ml of the standard solution by addingand dried until the temperature ofthe product was reached to 35 0.01 mol/liter ofhydrochloric acid reagent solution (Note: 3).46° C. The obtained dried granules were sized by passing to The test solutions and the standard solution were subjecteda sieve of 850 um. The dried granules contained 4.37% of to filtration, respectively by using a filter having microporeswater (measured by the method according to Reference of 10 to 20 pm in diameters, then each of the filtrates were

Example 4). introduced to a spectrophotometer installed with flow cell

b) The dried granules (200 g) obtained inExample 22-a) were 40 (cell length: 10 mm), and to measure the absorbance ofwave

charged in a fluidized bed dryer (multiplex, MP-01: manu- length at 249 nm and absorbance of wave length at 325 lam

factured by POWREX CORPORATION), and dried at 85° C. and determined the differences between absorbances to

of inlet air temperature, air flow rate of 0.5 m3/min for 2 named as At10, At20, At30, At45, At60 and As, respectively.hours. The dried granules contained 3.50% of water (mea- After themeasurements, the test solutions ofT10, T20, T30sured by the method according to Reference Example 4). 45 and T45 were putback to the testvessels respectively. Further,c) The dried granules (100 g) obtained in Example 22-a) were similar procedures were conducted to other 5 samples ofthe

charged in a vacuum dryer (vacuum granulating dryer LCV- test solutions.232: manufactured by TABAI CO., LTD.), anddried 80° C. of

tray temperature, about 760 mmHg ofdegree ofvacuum for 2 Dissolution rate relating to the indicated amount

hours. The dried granules were further dried similarly for 6 so ofaripiprazole—Amount of the standard sample

hours. The dried granules contained 3.17% of water (the ofaripiprazole (mg)x211xAsx9/5x20/C

product being dried for 2 hours: measured by the method wherein,according to Reference Example 4). The further dried gran- At: At10, At20, At30, At45 or At60ules contained 2.88% ofwater (the product being dried for 6 As: standard solutionhours: measured by the method according to Reference 55 C: Indicated amount of aripiprazole (mg)Example 4). (Note:1) Water was added to 1.97 g of acetic acid (100) and

d) About 1% by weight ofmagnesium stearate was added to 9.15 g of sodium acetate.trihydrate to make 1000 ml ofthe sized granules being obtained in Example 22-b) and solution (0.1 mo1/1).mixed, then the mixed granules were supplied to a tablet (Note:2) Paddle methodmachine (Single type Tablet machine No. 2B: manufactured so (Note:3) Waterwas added to 100 ml of0.1 malhydrochloricby KIKUSUI SEISAKUSHO CO., LTD.), and tableted with acid (Note:4) to make 1000 ml ofsolution.

punch, there were obtained tablets, each having 191 mg of (Note:4) Water was added to 0.9 ml of hydrochloric acid to

weight. make 1000 ml of solution.

e) About 1% by weight ofmagnesium stearate was added to b) Method of Dissolution Test ofthe 30 Mg Tablet

the sized granules being obtained in Example 22-c) and 65 One tablet each of the pharmaceutical solid oral prepara-mixed, then the mixed granules were supplied to a tablet tions (containing 30 mg each of anhydrous aripiprazole or

machine (Single type Tablet machine No. 2B: manufactured hydrate) was tested by using 900 ml of acetic acid buffer


Copy provided


US 9,359,302 B237 38

solution (pH 4.5) (Note: 5) as the test solution, and to conduct TABLE 3-continuedthe test by rotating a paddle at 75 rpm in accordance with themethod of USP (United States Pharmacopoea) (Note: 6). Open at 25° C./60% RH Open at 40° C./75% RH

The test solutions obtained respectively from 10 minutes, After After20 minutes, 30 minutes 45 minutes and 60 minutes after the 5 Samples used Initial 6 months Initial 1 week

start oftest, were named as T10, T20, T30, T45 and T60.Tablet (30 mg) 97.0% 96.3% 94.7% 94.8%

On the other hand, about 0.05 g of the standard sample of of Examplearipiprazole was weighed accurately, and dissolved inethanol 17-0(95%) so as to made exactly 50 ml of the ethanol solution. TfabRletf(30 mg) 97.2% 95.3% 97.2% 97.8%

Twenty (20) ml of the ethanol solution was taken accurately, io oE plreenlce8-b)and prepared exactly 1000 ml of the standard solution by Tablet (30 mg) 97.8% 96.3% 97.8% 96.9%

adding 0.01 mol/liter of hydrochloric acid reagent solution ofReference

(Note: 7). Example 18-c)

The test solutions and standard solution were subjected to

filtration, respectively by using a filter having micropores of 15

10 to 20 nm in diameters, then each of the filtrates were TABLE 4introduced to a spectrophotometer in which a flow cell (celllength: 10 mm) was installed, and measured the absorbance Samples used Initial After 2 weeks

ofwave length at 249 nm and absorbance of wave length at20 Samples used Tablet 89.8% 66.9%

325 nm, and the difference between these absorbances were (30 mg) of Examplenamed as Atl 0, At20, At30, At45, At60 and As, respectively. I9-a)

After the measurements, the test solutions ofT10, T20, T30 Tablet (30 mg) of 79.8%Example 19-b)and T45 were put back respectively to the test vessels. Fur-Tablet (30 mg) of 85.9%

ther, similar procedures were conducted to other 5 samples of Example 19-c)the test solutions. 25

Dissolution rate relating to the indicated amount

ofaripiprazole=Amount of the standard sample TABLE 5ofaripiprazole (mg)xAtxAsx9/5x20/C

30 Samples used Initial After 2 weekswherein,

At: Atl0, At20, At30, At45 orAt60 Tablet (30 of 94.8% 94.7%

As: standard solution Example 18-a)Tablet (30 mg) of 93.7% 93.1%

C: Indicated amount ofaripiprazole (mg) Example 20

(Note:5) Water was added to 1.91 g of acetic acid (100) and Tablet (30 mg) of 94.8% 90.9%

2.99 g of sodium acetate.trihydrate to made 1000 ml of 35 Example 21

solution (0.05 mo1/1).(Note:6) Paddle method(Note:7) Water is added to 100 ml of 0.1 mo1/1 hydrochloric TABLE 6

acid (Note:8) to made 1000 ml of solution.

(Note:8) Water was added to 0.9 ml ofhydrochloric acid to 40 Samples used Initial After 1 weeks

make 1000 ml of solution. Tablet (30 mg) of 96.5% 84.5%Example 22-d)

TABLE 2 Tablet (30 mg) of 92.5% 74.4%

Example 22-e)Open at 25° C.160% RH Open at 40° C./75% RH 45 (dreid for 2 houts)

Tablet (30 mg) of 96.2% 83.4%

After After Example 22-e)Samples used Initial 6 months Initial 1 week (dreid for 6 hours)

Tablet (15 mg) 83.4% 44.3% 83.4% 44.1%ofReference 50 (Note: Dissolution tests in Table 5 were conducted similarlyExample 4 to the procedures in the above-mentioned "b) Method ofTablet (15 mg) 90.1% 61.9% 90.1% 65.2% dissolution test of the mg tablet" except that by using 900ofReference

Example 5 ml of acetic acid buffer solution (pH 4.0) as the test solu-

tion, and by rotating a paddle at 50 rpm.55 As can be seen clearly from the data shown in Table 2, in

TABLE 3 comparison with the 15 mg tablet containing conventionalanhydrous aripiprazole mystals (Reference Example 4), the

Open at 25° C.160% RH Open at 40° C175% RH 15 mg tablet containing type B crystals of anhydrous arip-iprazole (Reference Example 5) had the dissolution rate to

After After 60 maintain maximum drug concentration (Cmax), at pH 5.0Samples used Initial 6 months Initial 1 week after 60 minutes, even though such tablet was kept under theTablet (30 mg) 96.7% 77.1% 96.7% 75.9% open at 25° C./60% RH for 6 months and under the open atof Example 40° C./75% RH for 1 week.18-a) As canbe seen clearly fromthe data shown inTable 3, evenTablet (30 mg) 96.5% 93.6% 95.0% 92.2%of Example 65 though 30 mg tablets (Examples 17-b) and 17-c)) prepared17-b) from twice dried granules of type B crystals of anhydrous

aripiprazole, and 30 mg tablets (Examples 18-b) and 18-c))


Copy provided


US 9,359,302 B239 40

prepared from further dried pharmaceutical solid oral prepa- In accordance with an ordinary method, tablet preparation,ration containing type B crystals of anhydrous aripiprazole containing the above-mentioned ingredients per 1 tablet was

were subjected to keep under the open at 25° C./60% RH for prepared.6 months or 40° C./75% RH for 1 week, the dissolution rates Sample Preparation 4

of these tablets obtained 60 minutes after the test at pH 4.5 5

were not substantially lowered.As can be seen clearly from the data shown in Table 4, Type E crystals of 5 mg

anhydrous aripiprazolewhen 30 mg tablets (Examples 19-a), 19-b) and 19-c)) con- Starch 131 mg

tabling conventional anhydrous aripiprazole crystals were Magnesium stearate 4 mg

further dried and subjected to keep under open at 40° C175% 10 Lactose 60 mg

RH for 2 weeks, then the dissolution rates of the tablets Total 200 mgobtained 60 minutes after the test at pH 4.5 were the dissolu-tion rates to maintain maximum drug concentration (Cmax). In accordance with an ordinary method, tablet preparation,As can be seen clearly from the data shown in Table 5, 15 containing the above-mentioned ingredients per 1 tablet waswhen 30 mg tablet (Example 18-a)) containing type B crys- prepared.tals of anhydrous aripiprazole, 30 mg tablet (Example 20) Sample Preparation 5containing type C crystals of anhydrous aripiprazole and 30

mg tablet (Example 21) containing type D crystals of anhy-drous aripiprazole were subjected to keep under open at 40° 20 Type F crystals of 5 mg

C./75% RH for 2 weeks, then the dissolution rates of the anhydrous aripiprazole

tablets obtained 60 minutes after the test at pH 4.0 were not Starch 131 mgMagnesium stearate 4 mg

substantially lowered. Lactose 60 mgAs can be seen clearly from the data shown in Table 6,

when 30 mg tablets (Examples 22-d) and 22-e)) prepared 25 Total 200 mg

from granules of conventional aripiprazole hydrate beingtwice dried, and subjected to keep under open at 40° C./75% In accordance with an ordinary method, tablet preparation,RH for 1 week, then the dissolution rates of the tablets containing the above-mentioned ingredients per 1 tablet was

obtained 60 minutes after the test at pH 4.5 were the dissolu- prepared.tion rates to maintain maximum drug concentration (Cmax). 30 Sample Preparation 6

Sample Preparation 1

Type G crystals of 5 mganhydrous aripiprazole

Anhydrous aripiprazole 5 mg35

Starchagnesium stearate

131 mgcrystals B M 4 mgStarch 131 mg Lactose 60 mgMagnesium stearate 4 mg

200 mgalLactose 60 mg

TotTotal200 mg40 Inaccordance with an ordinary method, tablet preparation,

Tablets containing the above ingredients in each tablet containing the above-mentioned ingredients per 1 tablet was

were prepared by formulation methods known to one skilled prepared.in the art ofPharmaceutical formulation.Sample Preparation 2 45 FORMULATION EXAMPLE

Type C crystals of 5 mganhydrous aripiprazole The following examples used aripiprazole drug substanceStarch 131 mg made by first milling or pulverizing the conventional hydrateMagnesium stearate 4 mg 50 ofaripiprazole and thenheating it to formtheanhydrous formLactose 60 mg (anhydrous aripiprazole crystals B).Total 200 mg

Formulation Example 1

In accordance with an ordinary method, tablet preparation, 55 Flash-melt tablets were prepared as follows:containing the above-mentioned ingredients per 1 tablet was Intragranulation:prepared.Sample Preparation 3

gredientMg. per

In60 Percent w/w tabletType D crystals of 5 mganhydrous aripiprazole Xylitol (300) Xylisorb 26 52

Starch 131 mg Avicel® PH 102 12 24

Magnesium stearate 4 mg Calcium Silicate 43.35 86.7

Lactose 60 mg Crospovidone 3 6

Amorphous silica 2 4

Total 200 mg65 Aspartarne 2 4

Wild cherry flavor 0.15 0.3


Copy provided by USPTO

-01-89-Pagel D: 79

US 9,359,302 B2

41 42-continued -continued

Mg. per Mg. perIngredient Percent w/w tablet Ingredient Percent w/w tablet

5Tartaric acid 2 4 Tartaric acid 2 4Acesulfame K 2 4 Acesulfame K 2 4Magnesium stearate 0.25 0.5 Magnesium stearate 0.25 0.5

Total weight 92.75 185.5 Total weight 92.75 185.5

10

The ingredients except for the magnesium stearate were The ingredients except for the magnesium stearate wereblended in a commercial V-blender in geometric proportions blended in a commercial V-blender in geometric proportionsfor 5 minutes each until all were added. The magnesium for 5 minutes each until all were added. The magnesiumstearate was then added and the mixture blended for an addi- stearate was added and the mixture blended for an additionaltional three minutes. The blended formulation was corn- 15 three minutes. The blended formulation was compacted, and

pacted at a pressure of30-35 kgF/cm2 in a commercial corn- screened to form stable granules in accordance with the pro-pactor equipped with an orifice such that the compacts cedure ofFormulation Example 1.

therefrom are in the form ofribbons. The ribbons were passed Extragranulation Ingredients:through a 30 mesh (600 microns) screen to form stable gran-

20ules of about 150 to 400 microns.

Extragranulation Ingredients: Mg. perIngredient Percent w/w tablet

Intragranulation 92.75 185.5Mg. per Avicel® PH 200 3 6

Ingredient Percent w/w tablet 25 Crospovidone 4 8Magnesium stearate 0.25 0.5

Intragranulation 92.75 185.5Avicel® PH 200 3 6 Total weight 100 200Crospovidone 4 8

Magnesium stearate 0.25 0.5

30Total weight 100 200 The intragranulation was placed in the blender and the

Avicel® PH 200 and crospovidoneadded thereto and blendedfor five minutes. The magnesium stearate was thenadded and

The intragranulation was placed i® the blender and the the mixture blended for an additional three minutes to formAvicel PH 200 and crospovidone addedthereto and blended the final blend. Tablets compressed therefrom had a breakingfor five minutes. The magnesium stearate was then added and 35 force of2.0 kP (3.1 SCU) and disintegrated in 10 seconds inthe mixture blended for an additional three minutes to form 5 ml ofwater.the final blend. Tablets compressed therefrom had a breakingforce of2.3 kP (3.5 SCU) and disintegrated in 10 seconds in5 ml of water. The final blend formulation demonstrated Formulation Example 3

excellent flow and was free of other problems such as chip- 40

ping, capping and sticking. It has been found that utilizing Flash-melt tablets containing aripiprazole, an antischizo-Avicel® PH 102 for the intragranulation andAvicel0 PH 200 phrenic drug, were prepared as follows:for the extragranulation ingredient enhanced the quality of Intragranulationthe resultant tablets.

45

Mg. perFormulation Example 2 Ingredient Percent w/w tablet

Aripiprazole 15 30

Xylitol (300) Xylisorb 25 50Flash-melt tablets containing a combination oftwo grades so Avicel® PH 102 6 12

of calcium silicate were prepared as follows: Calcium Silicate 37 74

Intraganulation: Crospovidone 3 6

Amorphous silica 2 4

Aspartame 2 4

Wild cherry flavor 0.15 0.3Mg. per 55 Tartaric acid 2 4

Ingredient Percent w/w tablet Acesulfame K 2 4

Magnesium stearate 0.25 0.5Xylitol (300) Xylisorb 26 52Avicel® PH 102 12 24 Total weight 94.4 188.8Calcium Silicate 33.35 66.7

(crystalline, alpha 60triclinic)Hubersorb 600 NF 10 20 The ingredients except for the magnesium stearate were

(amorphous calcium blended in a commemial V-blender in geometric proportionssilicate) for 5 minutes each until all were added. The magnesiumCrospovidone 3 6 stearate was added and the mixture blended for an additionalAmorphous silica 2 4

Aspartame 2 4 65 three minutes. The blended formulationwas compacted, andWild cherry flavor 0.15 0.3 screened to form stable granules in accordance with the pro-

cedure ofFormulation Example 1.

from the PIRS Image Database on 0811012016

Case-1:16=cv---05400-JBS-KMW Document 1-3 Filed 09102/16--P4-e 68 of 89 PagelD: 80

US 9,359,302 B2

43 44Extragranulation Ingredients: The invention claimed is:

1. Anhydrous aripiprazole crystals having low hygroscop-icity, wherein said low hygroscopicity is defined as a moisture

Mg. per content of 0.40% or less when the anhydrous aripiprazoleIngredient Percent w/w tablet 5 crystals are placed for 24 hours in a dessicator maintained at

Intragranulation 94.4 188.8 a temperature of 60° C. and a humidity level of 100%,Avice10 PH 200 1.1 2.2 wherein the anhydrous aripiprazole crystals have one or

Crospovidone 4 8 more of the following properties:Magnesium stearate 0.5 1

a powder x-ray diffraction spectrum comprising character-

Total weight 100 200 10 istic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°,using a Cu Ke, x-ray;

an infrared absorption spectrum comprising infraredThe intragranulation was placed in the blender and the absorption bands at 2945, 2812, 1678, 1627, 1448, 1377,

Avicel® PH 200 and crospovidone added thereto and blended 1173, 960, and 779 cm' on the IR (KBr) spectrum;for five minutes. The magnesium stearate was then added and rs an endothermic curve comprising an endothermic peak atthe mixture blended for an additional three minutes to form about 141.5° C. in a thermogravimetric or differentialthe final blend. Tablets compressed therefrom had a breaking thermal analysis (heating rate 5° C./min); andforce of2.0 kP (3.1 SCU) and disintegrated in 10 seconds in an endothermic curve comprising an endothermic peak at

5 ml ofwater. about 140.7° C. in a differential scanning calorimetry20 analysis (heating rate 5° Cimin).

Formulation Example 4 2. The anhydrous aripiprazole crystals according to claim1, wherein the anhydrous aripiprazole crystals have a mean

Flash-melt tablets containing aripiprazole were prepared particle size of 50 gm or less.as follows: 3. The anhydrous aripiprazole crystals according to claim

Intragranulation: 25 1, wherein the anhydrous aripiprazole crystals have a mean

particle size of50 fun or less, wherein the mean particle sizeis measured using a laser diffraction particle size analyzer.

Mg. per 4. The anhydrous aripiprazole crystals according to claimIngredient Percent w/w tablet 1, wherein the anhydrous aripiprazole crystals have a mean

Aripiprazole 0.5 1 30 particle size of 50 nm or less, wherein the mean particle size

Xylitol (300) Xylisorb 27 54 is measured using a laser diffraction particle size analyzer bYAvicele PH 102 12 24 suspending 0.1 g ofsaid anhydrous aripiprazole crystals in aCalcium Silicate 42 ga 20 mL n-hexane solution of0.5 g soy lecithin.Crospovidone 3 6Amorphous silica 2 4 5. The anhydrous aripiprazole crystals according to claim

Aspartame 2 4 35 1, wherein the anhydrous aripiprazole crystals have a mean

Wild cherry flavor 0.15 0.3 particle size of30 gm or less.Tartaric acid 2 4 6. The anhydrous aripiprazole crystals according to claimAcesulfame K 2 4

Magnesium stearate 0.25 0.5 1, wherein the anhydrous aripiprazole crystals have a mean

particle size of30 nm or less, wherein the mean particle sizeTotal weight 92.9 185.8 ao is measured using a laser diffraction particle size analyzer.

7. The anhydrous aripiprazole crystals according to claim1, wherein the anhydrous aripiprazole crystals have a meanThe ingredients except for the magnesium stearate wereparticle size of30 jim or less, wherein the mean particle size

blended in a commercial V-blender in geometric proportions is measured using a laser diffraction particle size analyzer byfor 5 minutes each until all were added. The magnesiumas suspending 0.1 g ofsaid anhydrous aripiprazole crystals in a

stearate was added and the mixture blended for an additional20 mL n-hexane solution of0.5 g soy lecithin.three minutes. The blended formulation was compacted, and

8. The anhydrous aripiprazole crystals according to claimscreened to form stable granules in accordance with the pro- 1, wherein the anhydrous aripiprazole crystals have a powdercedure of Formulation Example 1.

Extragranulation Ingredients: x-ray diffraction spectrum comprising characteristic peaks at

so 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°, using a Cu lc x-ray.9. The anhydrous aripiprazole crystals according to claim

1, wherein the anhydrous aripiprazole crystals have an infra-Mg. per

Ingredient Percent w/w tablet red absorption spectrum comprising infrared absorptionbands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960, and

Intragranulation 92.9 185.855 779 cm-1 on the IR (KBr) spectrum.Avicele PH 200 2.6 5.2

Crospovidone 4 8 10. The anhydrous aripiprazole crystals according to claim

Magnesium stearate 0.5 1 1, whereinthe anhydrous aripiprazole crystals have an endot-hermic curve comprising an endothermic peak at about

Total weight 100 200 141.5° C. in a thermogravimetric or differential thermal60 analysis (heating rate 5° C./min).

The intragranulation was placed in the blender and the 11. Theanhydrous aripiprazole crystals according to claim

Avicel® PH 200 and crospovidone addedthereto and blended 1, wherein the anhydrous aripiprazole crystals have an endot-for five minutes. The magnesium stearate was then added and hermic curve comprising an endothermic peak at about

the mixture blended for an additional three minutes to form 140.7° C. in a differential scanning calorimetry analysisthe final blend. Tablets compressed therefrom had a breaking 65 (heating rate 5° C./min).force of 2.3 kP (3.5 SCU) and disintegrated in 10 seconds in 12. Anhydrous aripiprazole crystals having low hygro-5 ml of water. scopicity, wherein said low hygroscopicity is defined as a


Case 1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16—Page 69 of 89 PagelD: 81

US 9,359,302 B245 46

moisture content of0.40% or less when the anhydrous arip- 23. The anhydrous aripiprazole crystals according to claimiprazole crystals are placed for 24 hours in a dessicator main- 19, wherein the anhydrous aripiprazole crystals have a mean

tained at a temperature of 60° C. and a humidity level of particle size of 30 pm or less.

100%, 24. The anhydrous aripiprazole crystals according to claimwherein the anhydrous aripiprazole crystals have a powder 5 19, wherein the anhydrous aripiprazole crystals have a mean

x-ray diffraction spectrum which is substantially the particle size of30 pm or less, wherein the mean particle sizesame as the powder x-ray diffraction spectrum shown in is measured using a laser diffraction particle size analyzer.FIG. 5 using a Cu Ku x-ray. 25. The anhydrous aripiprazole crystals according to claim

13. The anhydrous aripiprazole crystals according to claim 19, wherein the anhydrous aripiprazole crystals have a mean

12, wherein the anhydrous aripiprazole crystals have a mean to particle size of30 pm or less, wherein the mean particle size

particle size of 50 gm or less. is measured using a laser diffraction particle size analyzer by14. The anhydrous aripiprazole crystals according to claim suspending 0.1 g ofsaid anhydrous aripiprazole crystals in a

12, wherein the anhydrous aripiprazole crystals have a mean 20 mL n-hexane solution of0.5 g soy lecithin.particle size of 50 pm or less, wherein the mean particle size 26. The anhydrous aripiprazole crystals according to claimis measured using a laser diffraction particle size analyzer. 15 19, wherein the anhydrous aripiprazole crystals have a pow-

15. The anhydrous aripiprazole crystals according to claim der x-ray diffraction spectrum comprising characteristic

12, wherein the anhydrous aripiprazole crystals have a mean peaks at 20=11.00, 16.6°, 19.30, 20.3°, and 22.10, using a Cu

particle size of 50 pm or less, wherein the mean particle size K x-ray.is measured using a laser diffraction particle size analyzer by 27. The anhydrous aripiprazole crystals according to claim

suspending 0.1 g ofsaid anhydrous aripiprazole crystals in a 20 19, wherein the anhydrous aripiprazolecrystals have an infra-20 mL n-hexane solution of 0.5 g soy lecithin, red absorption spectrum comprising infrared absorption

16. The anhydrous aripiprazole crystals according to claim bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960, and12, wherein the anhydrous aripiprazole crystals have a mean 779 cm-1 on the IR (KBr) spectrum.particle size of 30 pm or less. 28. Theanhydrous aripiprazole crystals according to claim

17. The anhydrous aripiprazole crystals according to claim 25 19, wherein the anhydrous aripiprazole crystals have an

12, wherein the anhydrous aripiprazole crystals have a mean endothermic curve comprising an endothermic peak at aboutparticle size of30 pm or less, wherein the mean particle size 141.5° C. in a thermogpvimetric or differential thermalis measured using a laser diffraction particle size analyzer. analysis (heating rate 5° C./min).

18. The anhydrous aripiprazole crystals according to claim 29. The anhydrous aripiprazole crystals according to claim12, wherein the anhydrous aripiprazole crystals have a mean 30 19, wherein the anhydrous aripiprazole crystals have an

particle size of 30 pm or less, wherein the mean particle size endothermic curve comprising an endothermic peak at aboutis measured using a laser diffraction particle size analyzer by 140.7° C. in a differential scanning calorimetry analysissuspending 0.1 g ofsaid anhydrous aripiprazole crystals in a (heating rate 5° C./min).20 mL n-hexane solution of 0.5 g soy lecithin. 30. Anhydrous aripiprazole crystals having low hygro-

19. Anhydrous aripiprazole crystals having low hygro- 35 scopicity, wherein said low hygroscopicity is defined as a

scopicity, wherein said low hygroscopicity is defined as a moisture content of 0.10% or less when the anhydrous arip-moisture content of0.10% or less when the anhydrous aripiprazole crystals are placed for 24 hours in a dessicator main-

iprazole crystals are placed for 24 hours in a dessicator maintained at a temperature of 60° C. and a humidity level ofMined at a temperature of 60° C. and a humidity level of 100%,1009'o, 40 wherein the anhydrous aripiprazole crystals have a powder

wherein the anhydrous aripiprazole crystals have one or x-ray diffraction spectrum which is substantially themore of the following properties: same as the powder x-ray diffraction spectrum shown in

a powder x-ray diffraction spectrum comprisingcharacter- FIG. 5 using a Cu K, x-ray.istic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.10, 31. Theanhydrous aripiprazole crystals according to claimusing a Cu Kc, x-ray; 45 30, wherein the anhydrous aripiprazole crystals have a mean

an infrared absorption spectrum comprising infrared particle size of 50 pm or less.

absorptionbands at 2945, 2812, 1678, 1627, 1448, 1377, 32. The anhydrous aripiprazole crystals according to claim

1173, 960, and 779 cncl on the IR (KBr) spectrum; 30, wherein the anhydrous aripiprazole crystals have a mean

an endothermic curve comprising an endothermic peak at particle size of 50 pm or less, wherein the mean particle sizeabout 141.5° C. in a thermogravimetric or differential so is measured using a laser diffraction particle size analyzer.thermal analysis (heating rate 5° C./min); and 33. Theanhydrous aripiprazole crystals according to claim

an endothermic curve comprising an endothermic peak at 30, wherein the anhydrous aripiprazole crystals have a mean

about 140.7° C. in a differential scanning calorimetry particle size of50 pm or less, wherein the mean particle size

analysis (heating rate 5° C./min). is measured using a laser diffraction particle size analyzer by20. The anhydrous aripiprazole crystals according to claim 55 suspending 0.1 g ofsaid anhydrous aripiprazole crystals in a

19, wherein the anhydrous aripiprazole crystals have a mean 20 mL n-hexane solution of0.5 g soy lecithin.

particle size of 50 pm or less. 34. The anhydrous aripiprazole crystals according to claim21. The anhydrous aripiprazole crystals according to claim 30, wherein the anhydrous aripiprazole crystals have a mean

19, wherein the anhydrous aripiprazole crystals have a mean particle size of30 pm or less.

particle size of 50 pm or less, wherein the mean particle size 60 35. Theanhydrous aripiprazole crystals according to claimis measured using a laser diffraction particle size analyzer. 30, wherein the anhydrous aripiprazole crystals have a mean

22. The anhydrous aripiprazole crystals according to claim particle size of30 pm or less, wherein the mean particle size

19, wherein the anhydrous aripiprazole crystals have a mean is measured using a laser diffraction particle size analyzer.particle size of 50 pm or less, wherein the mean particle size 36. The anhydrous aripiprazole crystals according to claim

is measured using a laser diffraction particle size analyzer by 65 30, wherein the anhydrous aripiprazole crystals have a mean

suspending 0.1 g ofsaid anhydrous aripiprazole crystals in a particle size of30 pm or less, wherein the mean particle size

20 mL n-hexane solution of 0.5 g soy lecithin, is measured using a laser diffraction particle size analyzerby


Copy provided

Case 1:16-cv-05400-JBS-KMW-Document 1-3 Filed 09/02/16 Page 70 of 89 PagelD: 82

US 9,359,302 B247 48

suspending 0.1 g of said anhydrous aripiprazole crystals in a an infrared absorption spectrum comprising infrared20 mL n-hexane solution of 0.5 g soy lecithin, absorption bands at 2951, 2822, 1692, 1577, 1477, 1378,

37.A process for preparing anhydrous aripiprazole crystals 1187, 963, and 784 cm-1 on the IR (KBr) spectrum,having low hygroscopicity, wherein said process comprises wherein said low hygroscopicity is defined as a moisture

heating hydrous aripiprazole having one or more of the fol- 5 content of 0.10% or less when the anhydrous aripipra-lowing properties: zole crystals are placed for 24 hours in a dessicator

maintained at a temperature of 60° C. and a humiditya powder x-ray diffraction spectrum comprising character-

istic peaks at 20=12.6°, 15.40, 17.3°, 18.0°, 18.6°, 22.5°, level of 100%,and 24.8° using a Cu Kx-ray; wherein the anhydrous aripiprazole crystals have one or

a

an endothermic curve comprising a first endothermic peak to more of the following properties:a powder x-ray diffraction spectrum comprising charac-

at about 71° C. and a second endothermic peak aroundteristic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and

60° to 120° C. in a thermogravirnetric or differential22.1°, using a Cu Ka x-ray;

thermal analysis (heating rate 5° C./min); andan infrared absorption spectrum comprising infrared

an infrared absorption spectrum comprising infraredis absorption bands at 2945, 2812, 1678, 1627, 1448,

absorption bands at 2951, 2822, 1692, 1577, 1477, 1378, 1377, 1173, 960, and 779 cra-1 on the IR (KBr) spec-1187, 963, and 784 cm-1 on the IR (KBr) spectrum, trim;

wherein said low hygroscopicity is defined as a moisture an endothermic curve comprising an endothermic peakcontent of 0.40% or less when the anhydrous aripipra- at about 141.5° C. in a thermogravimetric or differen-zole crystals are placed for 24 hours in a dessicator zo tial thermal analysis (heating rate 5° C./min); andmaintained at a temperature of 60° C. and a humidity an endothermic curve comprising an endothermic peaklevel of 100%, at about 140.7° C. in a differential scanning calorirn-

wherein the anhydrous aripiprazole crystals have one or etry analysis (heating rate 5° C./min).more of the following properties: 43. The process according to claim 42, wherein the anhy-a powderx-ray diffraction spectrum comprising charac- 25 drous aripiprazole crystals have a powder x-ray diffraction

teristic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and spectrum comprising characteristic peaks at 20=11.00, 16.6°,22.1°, using a Cu Ka x-ray; 19.3°, 20.3°, and 22.1°, using a Cu Ka x-ray.

an infrared absorption spectrum comprising infrared 44. The process according to claim 42, wherein the anhy-absorption bands at 2945, 2812, 1678, 1627, 1448, drous aripiprazole crystals have an infrared absorption spec-

30 trum comprising infrared absorption bands at 2945, 2812,1377, 1173, 960, and 779 cm-1 on the IR (KBr) spec-1678, 1627, 1448, 1377, 1173, 960, and 779 cm-1 on the IR

trum;an endothermic curve comprising an endothermic peak (KBr) spectrum.

45. The process according to claim 42, wherein the anhy-at about 141.5° C. in a thermogravimetric or differen- drous aripiprazole crystals have an endothermic curve com-tial thermal analysis (heating rate 5° C./min); and

35 prising an endothermic peak at about 141.5° C. in a thermo-an endothermic curve comprising an endothennic peak gravimetric or differential thermal analysis (heating rate 5°

at about 140.7° C. in a differential scanning calorirn- cietry analysis (heating rate 5° C./min). 46. The process according to claim 42, wherein the anhy-

38. The process according to claim 37, wherein the anhydrous aripiprazole crystals have an endothermic curve com-

drous aripiprazole crystals have a powder x-ray diffraction 40 prising an endothermic peak at about 140.7° C. in a differen-

spectrum comprising characteristic peaks at 20=11.00, 16.6°, tial scanning calorimetry analysis (heating rate 5° C./min).19.3°, 20.3°, and 22.1°, using a Cu Ka x-ray. 47.Aprocess for preparing anhydrous aripiprazolecrystals

39. The process according to claim 37, wherein the anhy- having low hygroscopicity, wherein said process comprisesdrous aripiprazole crystals have an infrared absorption spec- heating hydrous aripiprazole having one or more of the fol-trum comprising infrared absorption bands at 2945, 2812, 45 lowing properties:1678, 1627, 1448, 1377, 1173, 960, and 779 cm-1 on the IR a powder x-ray diffraction spectrum which is substantially(KBr) spectrum. the same as the powder x-ray diffraction spectrum

40. The process according to claim 37, wherein the anhy- shown in FIG. 3 using a Cu Ka x-ray; anddrous aripiprazole crystals have an endothermic curve com- an endothermic curve which is substantially the same as the

prising an endothermic peak at about 141.5° C. in a thermo- so thermogravimetric or differential thermal analysisgravimetric or differential thermal analysis (heating rate 5° (heating rate 5° C./min) curve shown in FIG. 1,C./min). wherein said low hygroscopicity is defined as a moisture

41. The process according to claim 37, wherein the anhy- content of 0.40% or less when the anhydrous aripipra-drous aripiprazole crystals have an endothermic curve com- zole crystals are placed for 24 hours in a dessicator

prising an endothermic peak at about 140.7° C. in a differen- 55 maintained at a temperature of 60° C. and a humiditytial scanning calorimetry analysis (heating rate 5° C./min). level of 100%,

42.A process forpreparing anhydrous aripiprazole crystals wherein the anhydrous aripiprazole crystals have a powderhaving low hygroscopicity, wherein said process comprises x-ray diffraction spectrum which is substantially the

heating hydrous aripiprazole having one or more of the fol- same as the powder x-ray diffraction spectrum shown in

lowing properties: 60 FIG. 5 using a Cu Ka x-ray.a powder x-ray diffraction spectrum comprising character- 48.Aprocess forpreparing anhydrous aripiprazolecrystals

istic peaks at 20=12.6°, 15.40, 17.30, 18.0°, 18.6°, 22.5°, having low hygroscopicity, wherein said process comprisesand 24.8° using a Cu Ka x-ray; heating hydrous aripiprazole having one or more of the fol-

an endothermic curve comprising a first endothermic peak lowing properties:at about 71° C. and a second endothermic peak around 65 a powder x-ray diffraction spectrum which is substantially60° to 120° C. in a thermogravimetric or differential the same as the powder x-ray diffraction spectrumthermal analysis (heating rate 5° C./min); and shown in FIG. 3 using a Cu Ka x-ray; and


Case 1:16-cv-05400-JBS-KMW Document1-3 Filed-09/02/16 Page 71 of 89 PagelD: 83

US 9,359,302 B249 50

an endothermic curve which is substantially the same as the 56. Theanhydrous aripiprazole crystals according to claimthermogravimetric or differential thermal analysis 54, wherein the anhydrous aripiprazole crystals have an infra-(heating rate 5° C./min) curve shown in FIG. 1, red absorption spectrum comprising infrared absorption

wherein said low hygroscopicity is defined as a moisture bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960, andcontent of 0.10% or less when the anhydrous aripipra- 5 779 cm' on the IR (KBr) spectrum.zole crystals are placed for 24 hours in a dessicator 57. The anhydrous aripiprazole crystals according to claimmaintained at a temperature of 60° C. and a humidity 54, wherein the anhydrous aripiprazole crystals have an

level of 100%, endothermic curve comprising an endothermic peak at aboutwherein the anhydrous aripiprazole crystals have a powder 141.5° C. in a thermogravimetric or differential thermal

x-ray diffraction spectrum which is substantially the m analysis (heating rate 5° C./min).same as the powder x-ray diffraction spectrum shown in 58. Theanhydrous aripiprazole crystals according to claimFIG. 5 using a Cu K„ x-ray. 54, wherein the anhydrous aripiprazole crystals have an

49. The process according to any one of claims 37 to 48, endothermic curve comprising an endothermic peak at aboutwherein said process comprises heating the hydrous aripipra- 15

140.7° C. in a differential scanning calorimetry analysiszole at 90-125° C. for about 3-50 hours. (heating rate 5° C./min).

50. The process according to claim 49, wherein said pro- 59. Anhydrous aripiprazole crystals having low hygro-cess comprises heating the hydrous aripiprazole at 100° C. for scopicity prepared by a process comprising heating hydrousabout 18 hours. aripiprazole having one or more of the following properties:

51. The process according to claim 49, wherein said pro- 20 a powderx-ray diffraction spectrum comprisingcharacter-cess comprises heating the hydrous aripiprazole at 100° C. for isticpeaks at 20=12.6°, 15.4°, 17.3°, 18.0°, 18.6°, 22.5°,about 24 hours. and 24.8° using a Cu Kx-ray;

52. The process according to claim 49, wherein said pro- an endothermic curve comprising a first endothermic peakcess comprises heating the hydrous aripiprazole at 120° C. for at about 71° C. and a second endothermic peak aroundabout 3 hours. 25 60° to 120° C. in a thermogravimetric or differential

53. The process according to claim 49, wherein said pro- thermal analysis (heating rate 5° C./min); andcess comprises heating the hydrous aripiprazole for about 18 an infrared absorption spectrum comprising infraredhours at 100° C. followed by additional heating for about 3 absorption bands at 2951, 2822, 1692, 1577, 1477, 1378,hours at 120° C. 1187, 963, and 784 cm' on the IR (KBr) spectrum,54. Anhydrous aripiprazole crystals having low hygro- 30 wherein said low hygroscopicity is defined as a moisturescopicity prepared by a process comprising heating hydrous content of 0.10% or less when the anhydrous aripipra-aripiprazole having one or more of the following properties: zole crystals are placed for 24 hours in a dessicator

a powder x-ray diffraction spectrum comprising character-istic peaks at 20=12.6°, 15.4°, 17.3°, 18.0°, 18.6°, 22.5°,

maintained at a temperature of 60° C. and a humidityand 24.8° using a CuKlevelof 100%,x-ray; 35

wherein the anhydrous aripiprazole crystals have one oran endothermic curve comprising a first endothermic peakat about 71° C. and a second endothermic peak around more of the following properties:60° to 120° C. in a thennogravimetric or differential a powder x-ray diffraction spectrum comprising charac-

thermal analysis (heating rate 5° C./min); and teristic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, andan infrared absorption spectrum comprising infrared 40 22.1°, using a Cu K“. x-ray;

absorption bands at 2951, 2822, 1692, 1577, 1477, 1378, an infrared absorption spectrum comprising infrared1187, 963, and 784 cria' on the IR (KBr) spectrum, absorption bands at 2945, 2812, 1678, 1627, 1448,

wherein said low hygroscopicity is defined as a moisture 1377, 1173, 960, and 779 cm-1 on the IR (KBr) spec-content of 0.40% or less when the anhydrous aripipra- trum;zole crystals are placed for 24 hours in a dessicator 45 an endothermic curve comprising an endothermic peakmaintained at a temperature of 60° C. and a humidity at about 141.5° C. in a thermogravimetric or differen-level of 100%, tial thermal analysis (heating rate 5° C./min); and

wherein the anhydrous aripiprazole crystals have one or an endothermic curve comprising an endothermic peakmore of the following properties: at about 140.7° C. in a differential scanning calorim-a powder x-ray diffraction spectrum comprising charac- so etly analysis (heating rate 5° C./min).

teristic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 60. Theanhydrous aripiprazole crystals according to claim22.1°, using a Cu lc x-ray; 59, wherein the anhydrous aripiprazole crystals have a pow-

an infrared absorption spectrum comprising infrared der x-ray diffraction spectrum comprising characteristicabsorption bands at 2945, 2812, 1678, 1627, 1448, peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°, using a Cu1377, 1173, 960, and 779 cm_i on the IR (KBr) spec- ss ic x-ray.trum; 61. Theanhydrous aripiprazole crystals according to claim

an endothermic curve comprising an endothermic peak 59, wherein the anhydrous aripiprazole crystals have an infra-at about 141.5° C. in a thermogravimetric or differen- red absorption spectrum comprising infrared absorptiontial thermal analysis (heating rate 5° C./min); and bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960, and

an endothermic curve comprising an endothermic peak 60 779 cm-1 on the IR (KBr) spectrum.at about 140.7° C. in a differential scanning calorim- 62. Theanhydrous aripiprazole crystals according to claimetty analysis (heating rate 5° C./min). 59, wherein the anhydrous aripiprazole crystals have an

55. The anhydrous aripiprazole crystals according to claim endothermic curve comprising an endothermic peak at about54, wherein the anhydrous aripiprazole crystals have a pow- 141.5° C. in a thermogravimetric or differential thermalder x-ray diffraction spectrum comprising characteristic 65 analysis (heating rate 5° C./min).peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°, using a Cu 63. Theanhydrous aripiprazolecrystals according to claimlc x-ray. 59, wherein the anhydrous aripiprazole crystals have an


Copy provided by USPTO from the PI


US 9,359,302 B251 52

endothermic curve comprising an endothermic peak at about a powder x-ray diffraction spectrumcomprising character-140.7° C. in a differential scanning calorimetry analysis istic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°,(heating rate 5° C/min), using a Cu Ka x-ray;

64. Anhydrous aripiprazole crystals having low hygro- an infrared absorption spectrum comprising infrared

scopicity prepared by a process comprising heating hydrous 5 absorptionbands at 2945, 2812, 1678, 1627, 1448, 1377,aripiprazole having one or more of the following properties: 1173, 960, and 779 cm-1 on the IR (KBr) spectrum;

a powder x-ray diffraction spectrum which is substantially an endothermic curve comprising an endothermic peak at

about 141.5° C. in a thermogravimetric or differentialthe same as the powder x-ray diffraction spectrumshown in FIG. 3 using a Cu Kx-ray; and thermal analysis (heating rate 5° C./min); and

a

to an endothermic curve comprising an endothermic peak atan endothe ic c e which is substantially the same as the

about 140.7° C. in a differential scanning calorimetrythermogravimetric or differential thermal analysis analysis (heating rate 5° C./min).(heating rate 5° Chnin) curve shown in FIG. 1, 72. The pharmaceutical composition according to claimwherein said low hygroscopicity is defined as a moisture 71, wherein the anhydrous aripiprazole crystals have a pow-

content of 0.40% or less when the anhydrous aripipra- 15 der x-ray diffraction spectrum comprising characteristiczole crystals are placed for 24 hours in a dessicator peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°, using a Cumaintained at a temperature of 60° C. and a humidity Ka x_ray.level of 100%, 73. The pharmaceutical composition according to claim

wherein the anhydrous aripiprazole crystals have a powder 71, wherein the anhydrous aripiprazolecrystals have an infra-x-ray diffraction spectrum which is substantially the 20 red absorption spectrum comprising infrared absorptionsame as the powder x-ray diffraction spectrum shown in bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960, andFIG. 5 using a Cu Ka, x-ray. 779 cm-1 on the IR (KBr) spectrum.

65. Anhydrous aripiprazole crystals having low hygro- 74. The pharmaceutical composition according to claim

scopicity prepared by a process comprising heating hydrous 71, wherein the anhydrous aripiprazole crystals have an

aripiprazole having one or more of the following properties: 25 endothermic curve comprising an endothermic peak at abouta powder x-ray diffraction spectrum which is substantially 141.5° C. in a thermogravimetric or differential thermal

the same as the powder x-ray diffraction spectrum analysis (heating rate 5° C./min).shown in FIG. 3 using a Cu Ka x-ray; and 75. The pharmaceutical composition according to claim

74, wherein the anhydrous aripiprazole crystals have ananendothermic curve whichis substantially the same as thethermogravimetric or differential thermal analysis 30 endothermic curve comprising an endothermic peak at about

140.7° C. in a differential scanning calorimetry analysis(heating rate 5° Chnin) curve shown in FIG. 1,wherein said low hygroscopicity is defined as a moisture (heating rate 5° C./min).

76. A pharmaceutical composition comprising anhydrouscontent of 0.10% or less when the anhydrous aripipra- aripiprazole crystals having low hygroscopicity and at leastzole crystals are placed for 24 hours in a dessicator

35 one pharmaceutically acceptable carrier, wherein said lowmaintained at a temperature of 60° C. and a humidity hygroscopicity is defined as a moisture content of 0.40% orlevel of 100%, less when the anhydrous aripiprazole crystals are placed for

wherein the anhydrous aripiprazole crystals have a powder 24 hours ina dessicator maintained at a temperature of 60° C.x-ray diffraction spectrum which is substantially the and a humidity level of 100%,same as the powder x-ray diffraction spectrum shown in 40 wherein the anhydrous aripiprazole crystals have a powderFIG. 5 using a Cu Ka x-ray. x-ray diffraction spectrum which is substantially the

66. The anhydrous aripiprazole crystals according to any same as the powder x-ray diffraction spectrum shown inone ofclaims 54 to 65, wherein said process comprises heat- FIG. 5 using a Cu Ka x-ray.ing the hydrous aripiprazole at 90-125° C. for about 3-50 77. The pharmaceutical composition according to any one

hours. 45 ofclaims 71 to 76, wherein said pharmaceutical composition67. The anhydrous aripiprazole crystals according to claim comprises the anhydrous aripiprazole crystals in an amount

66, wherein said process comprises heating the hydrous arip- effective to treat schizophrenia.iprazole at 100° C. for about 18 hours. 78. The pharmaceutical composition according to any one

68. The anhydrous aripiprazole crystals according to claim ofclaims 71 to 76, wherein said pharmaceutical composition66, wherein said process comprises heating the hydrous arip- so is in the form ofa solid oral tablet.

iprazole at 100° C. for about 24 hours. 79. The pharmaceutical composition according to claim69. The anhydrous aripiprazole crystals according to claim 78, wherein said solid oral tablet has at least one dissolution

66, wherein said process comprises heating the hydrous arip- rate selected from the group consisting of60% or more at pHiprazole at 120° C. for about 3 hours. 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes,

70. The anhydrous aripiprazole crystals according to claim 55 and 55% or more at pH 5.0 after 60 minutes.66, wherein said process comprises heating the hydrous arip- 80. The pharmaceutical composition according to any one

iprazole for about 18 hours at 100° C. followed by additional ofclaims 71 to 76, wherein said pharmaceutical compositionheating for about 3 hours at 120° C. is in the form ofan oral flashmelt tablet.

71. A pharmaceutical composition comprising anhydrous 81. The pharmaceutical composition according to claim

aripiprazole crystals having low hygroscopicity and at least 60 80, wherein said oral flashmelt tablet has at least one disso-one pharmaceutically acceptable carrier, wherein said low lution rate selected fromthe group consisting of60% ormore

hygroscopicity is defined as a moisture content of 0.40% or at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60less when the anhydrous aripiprazole crystals are placed for minutes, and 55% or more at pH 5.0 after 60 minutes.24 hours M a dessicator maintained at a temperature of60° C. 82. A pharmaceutical composition comprising anhydrousand a humidity level of 100%, 65 aripiprazole crystals having low hygroscopicity and at least

wherein the anhydrous aripiprazole crystals have one or one pharmaceutically acceptable carrier, wherein said lowmore of the following properties: hygroscopicity is defined as a moisture content of 0.10% or

RS Image Database on 08/10/2016

08/10/2016

Case 1:16-cv-05400-JBS=KMW—Duarmunt1-3 Filed 09-102116 Page/3 of 89 PagelD: 85

US 9,359,302 B253 54

less when the anhydrous aripiprazole crystals are placed for at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 6024 hours in a dessicator maintained at a temperature of 60° C. minutes, and 55% or more at pH 5.0 after 60 minutes.and a humidity level of 100%, 93. A method for the treatment of schizophrenia which

wherein the anhydrous aripiprazole crystals have one or comprises administering to a patient in need thereofan effec-

more of the following properties: 5 tive amount of anhydrous aripiprazole crystals having low

a powder x-ray diffraction spectrum comprising character- hygroscopicity, wherein said low hygroscopicity is defined as

istic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°, a moisture content of 0.40% or less when the anhydroususing a Cu K“ x-ray; aripiprazole crystals are placed for 24 hours in a dessicator

an infrared absorption spectrum comprising infrared maintained at a temperature of 60° C. and a humidity level of

absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 10 l 0°%'

1173, 960, and 779 cm-' on the IR (KBr) spectrum;wherein the anhydrous aripiprazole crystals have one or

more of the following properties:an endothermic curve comprising an endothermic peak at

a powder x-ray diffraction spectrum comprising character-about 141.5° C. M a thermogravimetric or differential istic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°,thermal analysis (heating rate 5° Cimin); and

15 using a Cu Kr, x-ray;an endothermic curve comprising an endothermic peak at

an infrared absorption spectrum comprising infraredabout 140.7° C. in a differential scanning calorimetry absorption bands at 2945, 2812, 1678, 1627, 1448, 1377,analysis (heating rate 5° C./min). 1173, 960, and 779 cnid on the IR (KBr) spectrum;

83. The pharmaceutical composition according to claim an endothermic curve comprising an endothermic peak at

82, wherein the anhydrous aripiprazole crystals have a pow- 20 about 141.5° C. in a thermogravimetric or differentialder x-ray diffraction spectrum comprising characteristic thermal analysis (heating rate 5° C./min); andpeaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°, using a Cu an endothermic curve comprising an endothermic peak at

Ko, x-ray. about 140.7° C. in a differential scanning calorimetry84. The pharmaceutical composition according to claim analysis (heating rate 5° C./min).

82, wherein the anhydrous aripiprazole crystals have an infra- 25 94. The method according to claim 93, wherein the anhy-red absorption spectrum comprising infrared absorption drous aripiprazole crystals have a powder x-ray diffractionbands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960, and spectrum comprising characteristic peaks at 20=11.00, 16.6°,779 cm-' on the IR (KBr) spectrum. 19.3°, 20.3°, and 22.1°, using a Cu Ke, x-ray.

85. The pharmaceutical composition according to claim 95. The method according to claim 93, wherein the anhy-82, wherein the anhydrous aripiprazole crystals have an 30 drous aripiprazole crystals have an infrared absorption spec-endothermic curve comprising an endothermic peak at about trum comprising infrared absorption bands at 2945, 2812,141.5° C. in a thermogavimetric or differential thermal 1678, 1627, 1448, 1377, 1173, 960, and 779 cm-' on the IR

analysis (heating rate 5° C./min). (KBr) spectrum.86. The pharmaceutical composition according to claim 96. The method according to claim 93, wherein the anhy-

82, wherein the anhydrous aripiprazole crystals have an 35 drous aripiprazole crystals have an endothermic curve com-

endothermic curve comprising an endothermic peak at about prising an endothermic peak at about 141.5° C. in a thermo-140.7° C. in a differential scanning calorimetry analysis gravimetric or differential thermal analysis (heating rate 5°

(heating rate 5° C./min). C./min).87. A pharmaceutical composition comprising anhydrous 97. The method according to claim 93, wherein the anhy-

aripiprazole crystals having low hygroscopicity and at least ao drous aripiprazole crystals have an endothermic curve com-

one pharmaceutically acceptable carrier, wherein said low prising an endothermic peak at about 140.7° C. in a differen-

hygroscopicity is defined as a moisture content of 0.10% or tial scanning calorimetry analysis (heating rate 5° C./min).less when the anhydrous aripiprazole crystals are placed for 98. A method for the treatment of schizophrenia which24 hours in a dessicator maintained at a temperature of 60° C. comprises administering to a patient in need thereofan effec-and a humidity level of 100%, 45 tive amount of anhydrous aripiprazole crystals having low

wherein the anhydrous aripiprazole crystals have a powder hygroscopicity, wherein said low hygroscopicity is defined as

x-ray diffraction spectrum which is substantially the a moisture content of 0.40% or less when the anhydroussame as the powder x-ray diffraction spectrum shown in aripiprazole crystals are placed for 24 hours in a dessicatorFIG. 5 using a Cu KT, x-ray. maintained at a temperature of 60° C. and a humidity level of

88. The pharmaceutical composition according to any one so 100%,ofclaims 82 to 87, wherein said pharmaceutical composition wherein the anhydrous aripiprazole crystals have a powdercomprises the anhydrous aripiprazole crystals in an amount x-ray diffraction spectrum which is substantially theeffective to treat schizophrenia. same as the powder x-ray diffiaction spectrum shown in

89. The pharmaceutical composition according to any one FIG. 5 using a Cu Ks, x-ray.ofclaims 82 to 87, wherein said pharmaceutical composition 55 99. A method for the treatment of schizophrenia whichis in the form of a solid oral tablet. comprises administering to a patient in need thereofan effec-

90. The pharmaceutical composition according to claim tive amount of anhydrous aripiprazole crystals having low

89, wherein said solid oral tablet has at least one dissolution hygroscopicity, whereinsaid low hygroscopicity is defined as

rate selected from the goup consisting of60% or more at pH a moisture content of 0.10% or less when the anhydrous4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes, 60 aripiprazole crystals are placed for 24 hours in a dessicatorand 55% or more at pH 5.0 after 60 minutes. maintained at a temperature of 60° C. and a humidity level of

91. The pharmaceutical composition according to any one 100%,ofclaims 82 to 87, wherein said pharmaceutical composition wherein the anhydrous aripiprazole crystals have one or

is in the form of an oral flashmelt tablet, more of the following properties:92. The pharmaceutical composition according to claim 65 a powderx-raydiffraction spectrum comprising character-

91, wherein said oral flashmelt tablet has at least one disso- istic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°,lution rate selected from the group consisting of60% or more using a Cu K“ x-ray;

Uopy proviaeo by USPTO from Me rirto image uaraoase on

US 9,359,302 B255 56

an infrared absorption spectrum comprising infrared 107. The method according to claim 105, wherein theabsorption bands at 2945, 2812, 1678, 1627, 1448, 1377, anhydrous aripiprazole crystals have an infrared absorption1173, 960, and 779 crn-1 on the IR (KBr) spectrum; spectrum comprising infrared absorption bands at 2945,

an endothermic curve comprising an endothermic peak at 2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm-1 on

about 141.5° C. in a thermogravimetric or differential 5 the IR (KBr) spectrum.thermal analysis (heating rate 5° C./min); and 108. The method according to claim 105, wherein the

an endothermic curve comprising an endothermic peak at anhydrous aripiprazole crystals have an endothermic curve

about 140.7° C. in a differential scanning calorimetry comprising an endothermic peak at about 141.5° C. in a

analysis (heating rate 5° C./rain). thermogravimetric or differential thermal analysis (heating100. The method according to claim 99, wherein the anhy- 10 rate 5C./rnin).

109. The method according to claim 105, wherein thedrous aripiprazole crystals have a powder x-ray diffractionanhydrous aripiprazole crystals have an endothermic curve

spectrum comprising characteristic peaks at 20=11.0°, 16.6°, comprising an endothermic peak at about 140.7° C. in a19.30, 20.3°, and 22.1°, using a Cu Ku x-ray. differential scanning calorimetry analysis (heating rate 5°

101. The method according to claim 99, wherein the anhy- 15 C./min).drous aripiprazole crystals have an infrared absorption spec- 110. A method for the treatment of schizophrenia whichtrum comprising infrared absorption bands at 2945, 2812, comprises administering to a patient in need thereof from1678, 1627, 1448, 1377, 1173, 960, and 779 cm-1 on the IR about 0.1 milligrams to about 10 milligrams of anhydrous(KBr) spectrum. aripiprazole crystals having low hygroscopicity per 1 kg of

102. The method according to claim 99, wherein the anhy- 20 body weight, wherein said low hygroscopicity is defined as a

drous aripiprazole crystals have an endothermic curve corn- moisture content of 0.40% or less when the anhydrous arip-prising an endothermic peak at about 141.5° C. in a thermo- iprazole crystals are placed for 24 hours in a dessicatormain-gravimetric or differential thermal analysis (heating rate 5° tained at a temperature of 60° C. and a humidity level ofChnin). 100%,

103. The method according to claim 99, wherein the anhy- 25 wherein the anhydrous aripiprazole crystals have a powderdrous aripiprazole crystals have an endothermic curve com- x-ray diffraction spectrum which is substantially theprising an endothermic peak at about 140.7° C. in a differen- same as the powder x-ray diffraction spectrum shown intial scanning calorimetry analysis (heating rate 5° Cimin). FIG. 5 using a Cu Ks, x-ray.

104. A method for the treatment of schizophrenia which 111. A method for the treatment of schizophrenia whichcomprises administering to a patient in need thereofan effec- 30 comprises administering to a patient in need thereof fromtive amount of anhydrous aripiprazole crystals having low about 0.1 milligrams to about 10 milligrams of anhydroushygroscopicity, wherein said low hygroscopicity is defined as aripiprazole crystals having low hygroscopicity per 1 kg ofa moisture content of 0.10% or less when the anhydrous body weight, wherein said low hygroscopicity is defined as a

aripiprazole crystals are placed for 24 hours in a dessicator moisture content of 0.10% or less when the anhydrous arip-maintained at a temperature of60° C. and a humidity level of 35 iprazole crystals are placed for 24 hours ina dessicatormain-100%, tained at a temperature of 60° C. and a humidity level of

wherein the anhydrous aripiprazole crystals have a powder 100%,x-ray diffraction spectrum which is substantially the wherein the anhydrous aripiprazole crystals have one or

same as the powder x-ray diffraction spectrum shown in more of the following properties:FIG. 5 using a Cu Ku x-ray. 40 a powder x-ray diffraction spectrum comprising character-

105. A method for the treatment of schizophrenia which istic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.10,comprises administering to a patient in need thereof from using a Cu Ks, x-ray;about 0.1 milligrams to about 10 milligrams of anhydrous an infrared absorption spectrum comprising infraredaripiprazole crystals having low hygroscopicity per 1 kg of absorptionbands at 2945, 2812, 1678, 1627, 1448, 1377,body weight, wherein said low hygroscopicity is defined as a 45 1173, 960, and 779 cm-1 on the IR (KBr) spectrum;moisture content of0.40% or less when the anhydrous arip- an endothermic curve comprising an endothermic peak at

iprazole crystals are placed for 24 hours in a dessicator main- about 141.5° C. in a thermogravimetric or differentialWined at a temperature of 60° C. and a humidity level of thermal analysis (heating rate 5° C./min); and100%, an endothermic curve comprising an endothennic peak at

wherein the anhydrous aripiprazole crystals have one or so about 140.7° C. in a differential scanning calorimetrymore of the following properties: analysis (heating rate 5° C./min).

a powder x-ray diffraction spectrum comprising character- 112. The method according to claim 111, wherein theistic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°, anhydrous aripiprazole crystals have a powder x-ray diffrac-using a Cu Ku x-ray; tion spectrum comprising characteristic peaks at 20=11.00,

an infrared absorption spectrum comprising infrared 55 16.6°, 19.3°, 20.3°, and 22.10, using a Cu Ku x-ray.absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 113. The method according to claim 111, wherein the1173, 960, and 779 crn-1 on the IR (KBr) spectrum; anhydrous aripiprazole crystals have an infrared absorption

an endothemaic curve comprising an endothermic peak at spectrum comprising infrared absorption bands at 2945,about 141.5° C. in a thermogravimetric or differential 2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cra-1 on

thermal analysis (heating rate 5° C./min); and 60 the IR (KBr) spectrum.an endothermic curve comprising an endothermic peak at 114. The method according to claim 111, wherein the

about 140.7° C. in a differential scanning calorimetry anhydrous aripiprazole crystals have an endothermic curve

analysis (heating rate 5° C./nain). comprising an endothermic peak at about 141.5° C. in a

106. The method according to claim 105, wherein the thermogravirnetric or differential thermal analysis (heatinganhydrous aripiprazole crystals have a powder x-ray diffrac- 65 rate 5° C./min).tion spectrum comprising characteristic peaks at 20=11.0°, 115. The method according to claim 111, wherein the

16.6°, 19.3°, 20.3°, and 22.10, using a Cu Ku x-ray. anhydrous aripiprazole crystals have an endothermic curve



Case 1:16-cv-05400-JBS-KMW—Dacument 1-3 Filed 09/02116 Page 75 of 89 PagelD: 87

US 9,359,302 B257 58

comprising an endothermic peak at about 140.7° C. in a wherein the anhydrous aripiprazole crystalshave a powderdifferential scanning calorimetry analysis (heating rate 5° x-ray diffraction spectrum which is substantially theC/min). same as the powder x-ray diffraction spectrum shown in

116. A method for the treatment of schizophrenia which FIG. 5 using a Cu Ka x-ray.comprises administering to a patient in need thereof from 5 123. A method for the treatment of schizophrenia whichabout 0.1 milligrams to about 10 milligrams of anhydrous comprises administering to a patient in need thereof a unitaripiprazole crystals having low hygroscopicity per 1 kg of dose comprising from about 1 milligram to about 100 milli-body weight, wherein said low hygroscopicity is defined as a grams of anhydrous aripiprazole crystals having low hygro-moisture content of 0.10% or less when the anhydrous arip- scopicity, wherein said low hygroscopicity is defined as a

iprazole crystals are placed for 24 hours in a dessicatormain- io moisture content of 0.10% or less when the anhydrous arip-tained at a temperature of 60° C. and a humidity level of iprazole crystals are placed for 24 hours in a dessicator main-100%, tained at a temperature of 60° C. and a humidity level of


same as the powder x-ray diffraction spectrum shown in 15 more of the following properties:FIG. 5 using a Cu Ka x-ray. a powder x-ray diffraction spectrum comprising character-

117. A method for the treatment of schizophrenia which istic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°,comprises administering to a patient in need thereof a unit using a Cu Ka x-ray;dose comprising from about 1 milligram to about 100 milli- an infrared absorption spectrum comprising infraredgrams of anhydrous aripiprazole crystals having low hygro- 20 absorptionbands at 2945, 2812, 1678, 1627, 1448, 1377,scopicity, wherein said low hygroscopicity is defined as a 1173, 960, and 779 cm' on the IR (KBr) spectrum;moisture content of0.40% or less when the anhydrous arip- an endothermic curve comprising an endothermic peak at

iprazole crystals are placed for 24 hours in a dessicator main- about 141.5° C. in a thermogravimetric or differentialMined at a temperature of 60° C. and a humidity level of thermal analysis (heating rate 5° Clmin); and

100%, 25 an endothermic curve comprising an endothermic peak at

wherein the anhydrous aripiprazole crystals have one or about 140.7° C. in a differential scanning calorimetrymore of the following properties: analysis (heating rate 5° CJmin).

a powder x-ray diffraction spectrum comprising character- 124. The method according to claim 123, wherein theistic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°, anhydrous aripiprazole crystals have a powder x-ray diffrac-using a Cu Ka x-ray; 30 tion spectrum comprising characteristic peaks at 20=11.0°,

an infrared absorption spectrum comprising infrared 16.6°, 19.3°, 20.3°, and 22.1°, using a Cu Ka x-ray.absorptionbands at 2945, 2812, 1678, 1627, 1448, 1377, 125. The method according to claim 123, wherein the1173, 960, and 779 cm-1 on the IR (KBr) spectrum; anhydrous aripiprazole crystals have an infrared absorption

an endothermic curve comprising an endothermic peak at spectrum comprising infrared absorption bands at 2945,about 141.5° C. in a thermogravimetric or differential 35 2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm-' on

thermal analysis (heating rate 5° C./min); and the IR (KBr) spectrum.an endothermic curve comprising an endothermic peak at 126. The method according to claim 123, wherein the

about 140.7° C. in a differential scanning calorimetry anhydrous aripiprazole crystals have an endotheimic curve

analysis (heating rate 5° C./min). comprising an endothermic peak at about 141.5° C. in a

118. The method according to claim 117, wherein the ao thennogravimetric or differential thermal analysis (heatinganhydrous aripiprazole crystals have a powder x-ray diffrac- rate 5° Clmin).tion spectrum comprising characteristic peaks at 20=11.0°, 127. The method according to claim 123, wherein the

16.6°, 19.3°, 20.3°, and 22.1°, using a Cu Ka x-ray. anhydrous aripiprazole crystals have an endothennic curve

119. The method according to claim 117, wherein the comprising an endothermic peak at about 140.7° C. in a

anhydrous aripiprazole crystals have an infrared absorption 45 differential scanning calorimetry analysis (heating rate 5°

spectrum comprising infrared absorption bands at 2945, C./min).2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm' on 128. A method for the treatment of schizophrenia whichthe IR (KBr) spectrum. comprises administering to a patient in need thereof a unit

120. The method according to claim 117, wherein the dose comprising from about 1 milligram to about 100 milli-

anhydrous aripiprazole crystals have an endothermic curve 50 grams of anhydrous aripiprazole crystals having low hygro-comprising an endothermic peak at about 141.5° C. in a scopicity, wherein said low hygroscopicity is defmed as a

thermogravimetric or differential thermal analysis (heating moisture content of0.10% or less when the anhydrous arip-rate 5° Clmin). iprazole crystals are placed for 24 hours in a dessicatormain-

121. The method according to claim 117, wherein the tained at a temperature of 60° C. and a humidity level of

anhydrous aripiprazole crystals have an endothermic curve 55 100%,comprising an endothermic peak at about 140.7° C. in a wherein the anhydrous aripiprazole crystals have a powderdifferential scanning calorimetry analysis (heating rate 5° x-ray diffraction spectrum which is substantially the

Cimin). same as the powder x-ray diffraction spectrum shown in122. A method for the treatment of schizophrenia which FIG. 5 using a Cu Ka x-ray.

comprises administering to a patient in need thereof a unit 60 129. A method for the treatment ofbipolar disorder whichdose comprising from about 1 milligram to about 100 milli- comprises administering to a patient in need thereofan effec-

grams of anhydrous aripiprazole crystals having low hygro- tive amount of anhydrous aripiprazole crystals having low

scopicity, wherein said low hygroscopicity is defined as a hygroscopicity, wherein said low hygroscopicity is defined as

moisture content of0.40% or less when the anhydrous arip- a moisture content of 0.40% or less when the anhydrousiprazole crystals are placed for 24 hours in a dessicator main- 65 aripiprazole crystals are placed for 24 hours in a dessicatortained at a temperature of 60° C. and a humidity level of maintained at a temperature of60° C. and a humidity level of100%, 100%,


0/2016


US 9,359,302 B2

59 60wherein the anhydrous aripiprazole crystals have one or 136. The method according to claim 135, wherein the

more of the following properties: anhydrous aripiprazole crystals have a powder x-ray diffrac-a powder x-ray diffraction spectrum comprising character- tion spectrum comprising characteristic peaks at 20=11.00,

istic peaks at 20=11.00, 16.6°, 19.3°, 20.3°, and 22.1°, 16.6°, 19.30, 20.3°, and 22.10, using a Cu Ka x-ray.using a Cu Ka x-ray; 5 137. The method according to claim 135, wherein the

an infrared absorption spectrum comprising infrared anhydrous aripiprazole crystals have an infrared absorptionabsorption bands at 2945, 2812, 1678, 1627, 1448, 1377, spectrum comprising infrared absorption bands at 2945,1173, 960, and 779 cm-1 on the IR (KBr) spectrum; 2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm-' on

an endothermic curve comprising an endothermic peak at the IR (KBr) spectrum.about 141.5° C. in a thermogravimetric or differential 10 138. The method according to claim 135, wherein thethermal analysis (heating rate 5° C./min); and

anhydrous aripiprazole crystals have an endothermic curvean endothermic curve comprising an endothermic peak at

comprising an endothermic peak at about 141.5° C. in aabout 140.7° C. in a differential scanning calorimetryanalysis (heating rate 5° C./min). thermogravimetric or differential thermal analysis (heating

n130. The method according to claim 129, wherein the israte 5° C./mi).

anhydrous aripiprazole crystals have a powder x-ray diffrac- 139. The method according to claim 135, wherein the

tion spectrum comprising characteristic peaks at 20=11.0°, anhydrous aripiprazole crystals have an endothernaic curve

16.6°, 19.30, 20.3°, and 22.10, using a Cu Ka x-ray. comprising an endothermic peak at about 140.7° C. in a

131. The method according to claim 129, wherein the differential scanning calorimetry analysis (heating rate 5°

anhydrous aripiprazole crystals have an infrared absorption 20 C./min).spectrum comprising infrared absorption bands at 2945, 140. A method for the treatment ofbipolar disorder which

2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm-' on comprises administering to a patient in need thereofan effec-the IR (KBr) spectrum. tive amount of anhydrous aripiprazole crystals having low

132. The method according to claim 129, wherein the hygroscopicity, wherein said low hygroscopicity is defined as

anhydrous aripiprazole crystals have an endothermic curve 25 a moisture content of 0.10% or less when the anhydrouscomprising an endothermic peak at about 141.5° C. in a aripiprazole crystals are placed for 24 hours in a dessicatorthermogravimetric or differential thermal analysis (heating maintained at a temperature of 60° C. and a humidity level ofrate 5° C./min). 100%,

133. The method according to claim 129, wherein the wherein the anhydrous aripiprazole crystals have a powderanhydrous aripiprazole crystals have an endothermic curve 30

x-ray diffraction spectrum which is substantially thecomprising an endothermic peak at about 140.7° C. in a

same as the powder x-ray diffraction spectrum shown indifferential scanning calorimetry analysis (heating rate 5°

FIG. 5 using a Cu Ka x-ray.C./min). 141. A method for the treatment ofbipolar disorder which134. A method for the treatment ofbipolar disorder which

35 comprises administering to a patient in need thereof fromcomprises administering to a patient in need thereofan effec-about 0.1 milligrams to about 10 milligrams of anhydroustive amount of anhydrous aripiprazole crystals having low

hygroscopicity, wherein said low hygroscopicity is defined as aripiprazole crystals having low hygroscopicity per 1 kg of

a moisture content of 0.40% or less when the anhydrous body weight, wherein said low hygroscopicity is defined as a

aripiprazole crystals are placed for 24 hours in a dessicator moisture content of0.40% or less when the anhydrous arip-maintained at a temperature of 60° C. and a humidity level of 40 iprazole crystals are placed for 24 hours in a dessicator main-

100%, tained at a temperature of 60° C. and a humidity level ofwherein the anhydrous aripiprazole crystals have a powder 100%,

x-ray diffraction spectrum which is substantially the wherein the anhydrous aripiprazole crystals have one or

same as the powder x-ray diffraction spectrum shown in more ofthe following properties:FIG. 5 using a Cu Ka x-ray. 45 a powder x-raydiffraction spectrum comprising character-

135. A method for the treatment ofbipolar disorder which istic peaks at 20=11.00, 16.6°, 19.3°, 20.3°, and 22.1°,comprises administering to a patient in need thereofan effec- using a Cu Ka x-ray;tive amount of anhydrous aripiprazole crystals having low an infrared absorption spectrum comprising infraredhygroscopicity, wherein said low hygroscopicity is defined as absorptionbands at 2945, 2812, 1678, 1627, 1448, 1377,a moisture content of 0.10% or less when the anhydrous so 1173, 960, and 779 cm-1 on the IR (KBr) spectrum;aripiprazole crystals are placed for 24 hours in a dessicator an endotherniic curve comprising an endothermic peak at

maintained at a temperature of60° C. and a humidity level of about 141.5° C. in a thermogravimetric or differential100%, thermal analysis (heating rate 5° C./min); and

wherein the anhydrous aripiprazole crystals have one or an endothermic curve comprising an endothermic peak at

more of the following properties: 55 about 140.7° C. in a differential scanning calorimetrya powder x-ray diffraction spectrum comprising character- analysis (heating rate 5° C./min).

istic peaks at 20=11.00, 16.6°, 19.3°, 20.3°, and 22.1°, 142. The method according to claim 141, wherein the

using a Cu Ka x-ray; anhydrous aripiprazole crystals have a powder x-ray diffrac-an infrared absorption spectrum comprising infrared tion spectrum comprising characteristic peaks at 20=11.0°,

absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 60 16.6°, 19.3°, 20.3°, and 22.10, using a Cu Ka x-ray.1173, 960, and 779 cm-' on the IR (KBr) spectrum; 143. The method according to claim 141, wherein the

an endothermic curve comprising an endothermic peak at anhydrous aripiprazole crystals have an infrared absorptionabout 141.5° C. in a thermogravimetric or differential spectrum comprising infrared absorption bands at 2945,thermal analysis (heating rate 5° C./min); and 2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm-I on

an endothermic curve comprising an endothermic peak at ss the IR (KBr) spectrum.about 140.7° C. in a differential scanning calorimetry 144. The method according to claim 141, wherein the

analysis (heating rate 5° C./min). anhydrous aripiprazole crystals have an endothermic curve


89Case-1-.16-cv-05400-JBS-KNAW Document 1-3 Filed 09/02/16 Page 77 ofB9-PagelD:

US 9,359,302 B261 62

comprising an endothermic peak at about 141.5° C. in a body weight, wherein said low hygroscopicity is defined as a

thermogravimetric or differential thermal analysis (heating moisture content of0.10% or less when the anhydrous arip-rate 5° C./min). iprazole crystals are placed for 24 hours in a dessicator main-

145. The method according to claim 141, wherein the tained at a temperature of 60° C. and a humidity level ofanhydrous aripiprazole crystals have an endothermic curve s 100%,comprising an endothermic peak at about 140.7° C. in a wherein the anhydrous aripiprazole crystals have a powderdifferential scanning calorimetry analysis (heating rate 5° x-ray diffraction spectrum which is substantially theC./min). same as the powder x-ray diffraction spectrum shown in

146. A method for the treatment ofbipolar disorder which FIG. 5 using a Cu Ka x-ray.comprises administering to a patient in need thereof from io 153. A method for the treatment ofbipolar disorder whichabout 0.1 milligrams to about 10 milligrams of anhydrous comprises administering to a patient in need thereof a unitaripiprazole crystals having low hygroscopicity per 1 kg of dose comprising from about 1 milligram to about 100 milli-body weight, wherein said low hygroscopicity is defined as a grams of anhydrous aripiprazole crystals having low hygro-moisture content of 0.40% or less when the anhydrous arip- scopicity, wherein said low hygroscopicity is defined as a

iprazole crystals are placed for 24 hours in a dessicator main- 15 moisture content of0.40% or less when the anhydrous arip-tained at a temperature of 60° C. and a humidity level of iprazole crystals are placed for 24 hours in a dessicator main-100%, tained at a temperature of 60° C. and a humidity level of


same as the powder x-ray diffraction spectrum shown in 20 more of the following properties:FIG. 5 using a Cu Ka x-ray. a powder x-ray diffraction spectrumcomprising character-

147. A method for the treatment ofbipolar disorder which istic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°,comprises administering to a patient in need thereof from using a Cu Ka x-ray;about 0.1 milligrams to about 10 milligrams of anhydrous an infrared absorption spectrum comprising infraredaripiprazole crystals having low hygroscopicity per 1 kg of 25 absorption bands at 2945, 2812, 1678, 1627, 1448, 1377,body weight, wherein said low hygroscopicity is defined as a 1173, 960, and 779 cra' on the IR (KBr) spectrum;moisture content of0.10% or less when the anhydrous arip- an endothermic curve comprising an endothermic peak at

iprazole crystals are placed for 24 hours in a dessicatormain- about 141.5° C. in a thermogravimetric or differentialtained at a temperature of 60° C. and a humidity level of thermal analysis (heating rate 5° C./min); and100%, 30 an endothermic curve comprising an endothemaic peak at

wherein the anhydrous aripiprazole crystals have one or about 140.7° C. in a differential scanning calorimetrymore of the following properties: analysis (heating rate 5° C/min).

a powder x-ray diffraction spectrum comprising character- 154. The method according to claim 153, wherein theistic peaks at 28=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°, anhydrous aripiprazole crystals have a powder x-ray diffrac-using a Cu Ka x-ray; 35 tion spectrum comprising characteristic peaks at 20=11.0°,

an infrared absorption spectrum comprising infrared 16.6°, 19.3°, 20.3°, and 22.1°, using a Cu Ka x-ray.absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 155. The method according to claim 153, wherein the1173, 960, and 779 cm-1 on the IR (KBr) spectrum; anhydrous aripiprazole crystals have an infrared absorption

an endothermic curve comprising an endothermic peak at spectrum comprising infrared absorption bands at 2945,about 141.5° C. in a thermogravimetric or differential 40 2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm-1 on


about 140.7° C. in a differential scanning calorimetry anhydrous aripiprazole crystals have an endotheimic curve


148. The method according to claim 147, wherein the 45 thermogravimetric or differential thermal analysis (heatinganhydrous aripiprazole crystals have a powder x-ray diffiac- rate 5° C./min).tion spectrum comprising characteristic peaks at 20=11.0°, 157. The method according to claim 153, wherein the

16.6°, 19.3°, 20.3°, and 22.1°, using a Cu Ka x-ray. anhydrous aripiprazole crystals have an endothermic curve


anhydrous aripiprazole crystals have an infrared absorption so differential scanning calorimetry analysis (heating rate 5°

spectrum comprising infrared absorption bands at 2945, C./min).2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm-' on 158. A method for the treatment of bipolar disorder whichthe IR (KBr) spectrum. comprises administering to a patient in need thereof a unit

150. The method according to claim 147, wherein the dose comprising from about 1 milligram to about 100 milli-anhydrous aripiprazole crystals have an endothermic curve 55 grams of anhydrous aripiprazole crystals having low hygro-comprising an endothermic peak at about 141.5° C. in a scopicity, wherein said low hygroscopicity is defined as a

thermogravimetric or differential thermal analysis (heating moisture content of 0.40% or less when the anhydrous arip-rate 5° C./min). iprazole crystals are placed for 24 hours in a dessicator main-

151. The method according to claim 147, wherein the tained at a temperature of 60° C. and a humidity level ofanhydrous aripiprazole crystals have an endothermic curve 60 100%,comprising an endothermic peak at about 140.7° C. in a wherein the anhydrous aripiprazole crystals have a powderdifferential scanning calorimetry analysis (heating rate 5° x-ray diffraction spectrum which is substantially theC./min). same as the powder x-ray diffraction spectrum shown in

152. A method for the treatment ofbipolar disorder which FIG. 5 using a Cu Ka x-ray.comprises administering to a patient in need thereof from 65 159. A method for the treatment ofbipolar disorder whichabout 0.1 milligrams to about 10 milligrams of anhydrous comprises administering to a patient in need thereof a unit

aripiprazole crystals having low hygroscopicity per 1 kg of dose comprising from about 1 milligram to about 100 milli-


0/2016


US 9,359,302 B263 64

grams of anhydrous aripiprazole crystals having low hygro- an infrared absorption spectrum comprising infraredscopicity, wherein said low hygroscopicity is defined as a absorptionbands at 2945, 2812, 1678, 1627, 1448, 1377,moisture content of 0.10% or less when the anhydrous arip- 1173, 960, and 779 cm' on the IR (KBr) spectrum;iprazole crystals are placed for 24 hours in a dessicator main- an endothermic curve comprising an endothermic peak at

tained at a temperature of 60° C. and a humidity level of 5 about 141.5° C. in a thermogravimetric or differential

100%, thermal analysis (heating rate 5° C./min); andwherein the anhydrous aripiprazole crystals have one or an endothermic curve comprising an endothermic peak at

more of the folloiving properties: about 140.7° C. in a differential scanning calorimetrya powder x-ray diffraction spectrum comprising character- analysis (heating rate 5° C./min).

istic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°, 10 166. The method according to claim 165, wherein the

using a Cu Ku x-ray; anhydrous aripiprazole crystals have a powder x-ray diffrac-an infrared absorption spectrum comprising infrared tion spectrum comprising characteristic peaks at 20=11.0°,

absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 16.6°, 19.3°, 20.3°, and 22.1°, using a Cu Ku x-ray.1173, 960, and 779 cm-' on the IR (KBr) spectrum; 15

167. The method according to claim 165, wherein thean endothermic curve comprising an endothermic peak at anhydrous aripiprazole crystals have an infrared absorption

about 141.5° C. in a thermogravimetric or differential spectrum comprising infrared absorption bands at 2945,thermal analysis (heating rate 5° C./min); and 2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm' on

an endothermic curve comprising an endothenrdc peak at the IR (KBr) spectrum.about 140.7° C. in a differential scanning calorimetry 20 168. The method according to claim 165, wherein theanalysis (heating rate 5° C./min). anhydrous aripiprazole crystals have an endothermic curve


anhydrous aripiprazole crystals have a powder x-ray diffrac- thermogravimetric or differential thermal analysis (heatingtion spectrum comprising characteristic peaks at 20=11.0°, rate 5° C./rnin).16.6°, 19.3°, 20.3°, and 22.1°, using a Cu Ku x-ray. 25 169. The method according to claim 165, wherein the

161. The method according to claim 159, wherein the anhydrous aripiprazole crystals have an endothermic curve

anhydrous aripiprazole crystals have an infrared absorption comprising an endothermic peak at about 140.7° C. in a

spectrum comprising infrared absorption bands at 2945, differential scanning calorimetry analysis (heating rate 5°

2812 1678, 1627, 1448, 1377, 1173, 960, and 779 cm' on C./min).the IR (KBr) spectrum.

30 170. A method for the treatment ofanxiety, depression, or

mania which comprises administering to a patient in need162. The method according to claim 159, wherein thethereof an effective amount of anhydrous aripiprazole crys-anhydrous aripiprazole crystals have an endothermic curve tals having low hygroscopicity, wherein said low hygroscop-comprising an endothermic peak at about 141.5° C. in a..Icily is defined as a moisture content of 0.40% or less when

themiogravimetric or differential thermal analysis (heating 35 the anhydrous aripiprazole crystals are placed for 24 hours inrate 5° C./min). a dessicator maintained at a temperature of 60° C. and a

163. The method according to claim 159, wherein the humidity level of 100%,anhydrous aripiprazole crystals have an endothermic curve wherein the anhydrous aripiprazole crystals have a powdercomprising an endothermic peak at about 140.7° C. in a x-ray diffraction spectrum which is substantially thedifferential scanning calorimetry analysis (heating rate 50 40 same as the powder x-ray diffraction spectrum shown inC./min). FIG. 5 using a Cu Ku x-ray.

164. A method for the treatment ofbipolar disorder which 171. A method for the treatment ofanxiety, depression, or

comprises administering to a patient in need thereof a unit mania which comprises administering to a patient in needdose comprising from about 1 milligram to about 100 milli- thereof an effective amount of anhydrous aripiprazole crys-grams of anhydrous aripiprazole crystals having low hygro- 45 tals having low hygroscopicity, wherein said low hygroscop-scopicity, wherein said low hygroscopicity is defined as a icity is defined as a moisture content of 0.10% or less whenmoisture content of0.10% or less when the anhydrous arip- the anhydrous aripiprazole crystals are placed for 24 hours iniprazole crystals are placed for 24 hours in a dessicator main- a dessicator maintained at a temperature of 60° C. and a

tained at a temperature of 60° C. and a humidity level of humidity level of 100%,100%, so wherein the anhydrous aripiprazole crystals have one or

wherein the anhydrous aripiprazole crystals have a powder more of the following properties:x-ray diffraction spectrum which is substantially the a powderx-ray diffraction spectrum comprising character-same as the powder x-ray diffraction spectrum shown in istic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°,FIG. 5 using a Cu Ku x-ray. using a Cu Ku x-ray;

165. A method for the treatment ofanxiety, depression, or 55 an infrared absorption spectrum comprising infraredmania which comprises administering to a patient in need absorption bands at 2945, 2812, 1678, 1627, 1448, 1377,thereof an effective amount of anhydrous aripiprazole crys- 1173, 960, and 779 clic' on the IR (KBr) spectrum;tals having low hygroscopicity, wherein said low hygroscop- an endothermic curve comprising an endothermic peak at

icity is defined as a moisture content of 0.40% or less when about 141.5° C. in a thermogravimetric or differentialthe anhydrous aripiprazole crystals are placed for 24 hours in 60 thermal analysis (heating rate 5° C./min); anda dessicator maintained at a temperature of 60° C. and a an endothermic curve comprising an endothermic peak at

humidity level of 100%, about 140.7° C. in a differential scanning calorimetrywherein the anhydrous aripiprazole crystals have one or analysis (heating rate 5° C./min).

more of the following properties: 172. The method according to claim 171, wherein thea powder x-ray diffraction spectrum comprising character- 65 anhydrous aripiprazole crystals have a powder x-ray diffrac-

istic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°, tion spectrum comprising characteristic peaks at 20=11.0°,using a Cu Ku x-ray; 16.6°, 19.3°, 20.3°, and 22.1°, using a Cu Ku x-ray.


08/10/2016


US 9,359,302 B265 66


anhydrous aripiprazole mystals have an infrared absorption differential scanning calorimetry analysis (heating rate 5°

spectrum comprising infrared absorption bands at 2945, C./rain).2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cniT' on 182. A method for the treatment ofanxiety, depression, or

the IR (KBr) spectrum. 5 mania which comprises administering to a patient in need174. The method according to claim 171, wherein the thereof from about 0.1 milligrams to about 10 milligrams of

anhydrous aripiprazole crystals have an endothermic curve anhydrous aripiprazole crystals having low hygroscopicitycomprising an endothermic peak at about 141.5° C. in a per 1 kg of body weight, wherein said low hygroscopicity is

defined as a moisture content of 0.40% or less when thethermogravimetric or differential thermal analysis (heatingrate 5° C./min). io anhydrous aripiprazole crystals are placed for 24 hours in a

des sicator maintained at a temperature of60° C. and a humid-175. The method according to claim 171, wherein the

ity level of 1130%,anhydrous aripiprazole crystals have an endothermic curve wherein the anhydrous aripiprazole crystals have a powdercomprising an endothermic peak at about 140.7° C. in ax-ray diffraction spectrum which is substantially the

differential scanning calorimetry analysis (heating rate 5°15 same as the powder x-ray diffraction spectrum shown in

C./rain). FIG. 5 using a Cu Ka x-ray.176. A method for the treatment ofanxiety, depression, or 183. A method for the treatment ofanxiety, depression, or

mania which comprises administering to a patient in need mania which comprises administering to a patient in needthereof an effective amount of anhydrous aripiprazole crys- thereof from about 0.1 milligrams to about 10 milligrams oftals having low hygroscopicity, wherein said low hygroscop- 20 anhydrous aripiprazole crystals having low hygroscopicityicity is defined as a moisture content of 0.10% or less when per 1 kg of body weight, wherein said low hygroscopicity isthe anhydrous aripiprazole crystals are placed for 24 hours in defined as a moisture content of 0.10% or less when thea dessicator maintained at a temperature of 60° C. and a anhydrous aripiprazole crystals are placed for 24 hours in a

humidity level of 100%, des sicator maintained at a temperature of60° C. and a humid-wherein the anhydrous aripiprazole crystals have a powder 25 ity level of 100%,

x-ray diffraction spectrum which is substantially the wherein the anhydrous aripiprazole crystals have one or

same as the powder x-ray diffraction spectrum shown in more of the following properties:FIG. 5 using a Cu Ka x-ray. a powder x-raydiffraction spectrum comprising character-

177. A method for the treatment ofanxiety, depression, or istic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°,mania which comprises administering to a patient in need 30 using a Cu Ka x-ray;thereof from about 0.1 milligrams to about 10 milligrams of an infrared absorption spectrum comprising infraredanhydrous aripiprazole crystals having low hygroscopicity absorption bands at 2945, 2812, 1678, 1627, 1448, 1377,per 1 kg of body weight, wherein said low hygroscopicity is 1173, 960, and 779 cm' on the IR (KBr) spectrum;defined as a moisture content of 0.40% or less when the an endothermic curve comprising an endothemiic peak at

anhydrous aripiprazole crystals are placed for 24 hours in a 35 about 141.5° C. in a thermogravimetric or differentialdessicator maintained at a temperature of60° C. and a humid- thermal analysis (heating rate 5° C./min); andity luvel of 100%, an endothermic curve comprising an endothemiic peak at

wherein the anhydrous aripiprazole crystals have one or about 140.7° C. in a differential scanning calorimetrymore of the following properties: analysis (heating rate 5° C./min).

a powder x-ray diffraction spectrum comprising character- ao 184. The method according to claim 183, wherein theistic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°, anhydrous aripiprazole crystals have a powder x-ray diffrac-using a Cu Ka x-ray; tion spectrum comprising characteristic peaks at 20=11.0°,

an infrared absorption spectrum comprising infrared 16.6°, 19.3°, 20.3°, and 22.1°, using a Cu Ka x-ray.absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 185. The method according to claim 183, wherein the1173, 960, and 779 cm-1 on the IR (KBr) spectrum; 45 anhydrous aripiprazole crystals have an infrared absorption

an endothermic curve comprising an endothermic peak at spectrum comprising infrared absorption bands at 2945,about 141.5° C. in a thermogravimetric or differential 2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm-"' on


about 140.7° C. in a differential scanning calorimetry so anhydrous aripiprazole crystals have an endothermic curve


178. The method according to claim 177, wherein the thermogravimetric or differential thermal analysis (heatinganhydrous aripiprazole crystals have a powder x-ray diffrac- rate 5° C./rain).tion spectrum comprising characteristic peaks at 20=11.0°, 187. The method according to claim 183, wherein the16.6°, 19.3°, 20.3°, and 22.1°, using a Cu Ka x-ray. 55 anhydrous aripiprazole crystals have an endothermic curve


anhydrous aripiprazole crystals have an infrared absorption differential scanning calorimetry analysis (heating rate 5°spectrum comprising infrared absorption bands at 2945, C./min).2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm-' on 188. A method for the treatment ofanxiety, depression, or

the IR (KBr) spectrum. 60 mania which comprises administering to a patient in need180. The method according to claim 177, wherein the thereof from about 0.1 milligrams to about 10 milligrams of

anhydrous aripiprazole crystals have an endothermic curve anhydrous aripiprazole crystals having low hygroscopicitycomprising an endothermic peak at about 141.5° C. in a per 1 kg ofbody weight, wherein said low hygroscopicity isthermogravimetric or differential thermal analysis (heating defined as a moisture content of 0.10% or less when therate 5° C./rain). 65 anhydrous aripiprazole crystals are placed for 24 hours in a

181. The method according to claim 177, wherein the dessicator maintained at a temperature of60° C. and a humid-anhydrous aripiprazole crystals have an endothermic curve ity level of 100%,


Copy provided 0/2016


US 9,359,302 B267 68

wherein the anhydrous aripiprazole crystals have a powder anhydrous aripiprazole crystals are placed for 24 hours in a

x-ray diffraction spectrum which is substantially the dessicator maintained at a temperature of60° C. and a humid-same as the powder x-ray diffraction spectrum shown in ity level of 100%,FIG. 5 using a Cu Ka x-ray. wherein the anhydrous aripiprazole crystals have one or

189. A method for the treatment ofanxiety, depression, or 5 more of the following properties:mania which comprises administering to a patient in need a powder x-ray diffraction spectrum comprising character-

thereof a unit dose comprising from about 1 milligram to istic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°,about 100 milligrams ofanhydrous aripiprazole crystals hav- using a Cu Ko, x-ray;

ing low hygroscopicity, wherein said low hygroscopicity is an infrared absorption spectrum comprising infraredro absorptionbands at 2945, 2812, 1678, 1627, 1448, 1377,defined as a moisture content of 0.40% or less when the

1173, 960, and 779 cm-1 on the IR (KBr) spectrum;anhydrous aripiprazole crystals are placed for 24 hours in aan endothermic curve comprising an endothermic peak at

dessicator maintained at a temperature of60° C. and a humid- about 141.5° C. in a thermogravimetric or differentiality level of 100%, thermal analysis (heating rate 5° C./min); and

wherein the anhydrous aripiprazole crystals have one or 15 an endothermic curve comprising an endothermic peak atmore of the following properties: about 140.7° C. in a differential scanning calorimetry

a powder x-ray diffraction spectrum comprising character- analysis (heating rate 5° C./min).istic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°, 196. The method according to claim 195, wherein theusing a Cu Ka x-ray; anhydrous aripiprazole crystals have a powder x-ray diffrac-

an infrared absorption spectrum comprising infrared 20 tion spectrum comprising characteristic peaks at 20=11.0°,absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 16.6°, 19.3°, 20.3°, and 22.1°, using a Cu Ka x-ray.1173, 960, and 779 cm-1 on the IR (KBr) spectrum; 197. The method according to claim 195, wherein the

an endothermic curve comprising an endothemfic peak at anhydrous aripiprazole crystals have an infrared absorptionabout 141.5° C. in a thermogravimetric or differential spectrum comprising infrared absorption bands at 2945,thermal analysis (heating rate 5° C./min); and 25 2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm-1 on

an endothermic curve comprising an endotheimic peak at the IR (KBr) spectrum.about 140.7° C. in a differential scanning calorimetry 198. The method according to claim 195, wherein the

analysis (heating rate 5° C./min). anhydrous aripiprazole crystals have an endothermic curve


30 thermogravimetric or differential thermal analysis (heatinganhydrous aripiprazole crystals have a powder x-ray diffrac-rate 5° C./min).tion spectrum comprising characteristic peaks at 20=11.0°, 199. The method according to claim 195, wherein the

16.6°, 19.3°, 20.3°, and 22.1°, using a Cu Ka x-ray. anhydrous aripiprazole crystals have an endothermic curve191. The method according to claim 189, wherein the comprising an endothennic peak at about 140.7° C. in a

anhydrous aripiprazole crystals have an infrared absorption 35 differential scanning calorimetry analysis (heating rate 5°spectrum comprising infrared absorption bands at 2945, C./2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm-1 on 200. A method for the treatment ofanxiety, depression, orthe IR (KBr) spectrum. mania which comprises administering to a patient in need

192. The method according to claim 189, wherein the thereof a unit dose comprising from about 1 milligram to

anhydrous aripiprazole crystals have an endothermic curve 40 about 100 milligrams ofanhydrous aripiprazole crystals hav-comprising an endothermic peak at about 141.5° C. in a ing low hygroscopicity, wherein said low hygroscopicity isthermogravimetric or differential thermal analysis (heating defined as a moisture content of 0.10% or less when therate 5° C./min). anhydrous aripiprazole crystals are placed for 24 hours in a

193. The method according to claim 189, wherein the dessicator maintained at a temperature of60° C. and a humid-anhydrous aripiprazole crystals have an endothermic curve 45 ity level of 100%,comprising an endothermic peak at about 140.7° C. in a wherein the anhydrous aripiprazole crystals have a powderdifferential scanning calorimetry analysis (heating rate 5° x-ray diffraction spectrum which is substantially the

C./min). same as the powderx-ray diffraction spectrum shown in194. A method for the treatment of anxiety, depression, or FIG. 5 using a Cu Ka x-ray.

mania which comprises administering to a patient in need so 201.A method forthe treatmentofautism whichcomprisesthereof a unit dose comprising from about 1 milligram to administering to a patient inneed thereofan effective amountabout 100 milligrams ofanhydrous aripiprazole crystals hav- of anhydrous aripiprazole crystals having low hygroscopic-ing low hygroscopicity, wherein said low hygroscopicity is ity, wherein said low hygroscopicity is defined as a moisturedefined as a moisture content of 0.40% or less when the content of 0.40% or less when the anhydrous aripiprazoleanhydrous aripiprazole crystals are placed for 24 hours in a 55 crystals are placed for 24 hours in a dessicator maintained at

dessicator maintained at a temperature of60° C. and a humid- a temperature of 60° C. and a humidity level of 100%,ity level of 100%, wherein the anhydrous aripiprazole crystals have one or

wherein the anhydrous aripiprazole crystals have a powder more of the following properties:x-ray diffraction spectrum which is substantially the a powder x-ray diffraction spectrum comprising character-same as the powder x-ray diffraction spectrum shown in 60 istic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°,FIG. 5 using a Cu Ka x-ray. using a Cu Ka x-ray;

195. A method for the treatment ofanxiety, depression, or an infrared absorption spectrum comprising infraredmania which comprises administering to a patient in need absorption bands at 2945, 2812, 1678, 1627, 1448, 1377,thereof a unit dose comprising from about 1 milligram to 1173, 960, and 779 cm-1 on the IR (KBr) spectrum;about 100 milligrams ofanhydrous aripiprazole crystals hay- 65 an endothermic curve comprising an endothermic peak at

ing low hygroscopicity, wherein said low hygroscopicity is about 141.5° C. in a thermogravimetric or differentialdefined as a moisture content of 0.10% or less when the thermal analysis (heating rate 5° C./min); and


Copy provided 08/10/2016

Case 1:16-cv-05400-JBS-KMW—Document 1-3 Filed 09102116 Page 81 of--89-Pagel

US 9,359,302 B269 70

an endothermic curve comprising an endothermic peak at comprising an endothermic peak at about 141.5° C. in a

about 140.7° C. in a differential scanning calorimetry thermogravimetric or differential thermal analysis (heatinganalysis (heating rate 5° C./min). rate 5° C./min).

202. The method according to claim 201, wherein the 211. The method according to claim 207, wherein theanhydrous aripiprazole crystals have a powder x-ray diffrac- 5 anhydrous aripiprazole crystals have an endothermic curve

tion spectrum comprising characteristic peaks at 20=11.0°, comprising an endothermic peak at about 140.7° C. in a

16.6°, 19.3°, 20.3°, and 22.1°, using a Cu K„ x-ray. differential scanning calorimetry analysis (heating rate 5°203. The method according to claim 201, wherein the C./min).

anhydrous aripiprazole crystals have an infrared absorption 212. A method forthe treatment ofautism whichcomprisesspectrum comprising infrared absorption bands at 2945, 1° administering to a patient inneed thereofan effective amount

2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm-I on of anhydrous aripiprazole crystals having low hygroscopic-the IR (KBr) spectrum. ity, wherein said low hygroscopicity is defined as a moisture

204. The method according to claim 201, wherein the content of 0.10% or less when the anhydrous aripiprazoleanhydrous aripiprazole crystals have an endothermic curve

is crystals are placed for 24 hours in a dessicator maintained at

comprising an endothermic peak at about 141.5° C. in a a temperature of60° C. and a humidity level of 100%,thermogravimetric or differential thermal analysis (heating wherein the anhydrous aripiprazole crystals have a powderrate 5° Cfrain). x-ray diffraction spectrum which is substantially the

205. The method according to claim 201, wherein the same as the powderx-ray diffraction spectrum shown inanhydrous aripiprazole crystals have an endothermic curve 20 FIG. 5 using a Cu K“ x-ray.comprising an endothermic peak at about 140.7° C. in a 213. Amethod for the treatment ofautism which comprisesdifferential scanning calorimetry analysis (heating rate 5° administering to a patient in need thereof from about 0.1

milligrams to about 10 milligrams ofanhydrous aripiprazole206.A method for the treatmentofautism which comprises crystals having low hygroscopicity per 1 kg ofbody weight,

administering to a patient in need thereofan effective amount 25 wherein said low hygroscopicity is defined as a moistureof anhydrous aripiprazole crystals having low hygroscopic- content of 0.40% or less when the anhydrous aripiprazoleity, wherein said low hygroscopicity is defined as a moisture crystals are placed for 24 hours in a dessicator maintained at

content of 0.40% or less when the anhydrous aripiprazole a temperature of60° C. and a humidity level of 100%,crystals are placed for 24 hours in a dessicator maintained at wherein the anhydrous aripiprazole crystals have one or

a temperature of 60° C. and a humidity level of 100%, 30 more of the following properties:a powder x-ray diffraction spectrum comprising character-wherein the anhydrous aripiprazole crystals have a powder istic peaks

x-ray diffraction spectrum which is substantially theusing a Cu x-ray;

same as the powder x-ray diffraction spectrum shown inan infrared absorption spectrum comprising infrared

FIG. 5 using a Cu Kc, x-ray. 35 absorption bands at 2945, 2812, 1678, 1627, 1448, 1377,267.A method for the treatmentofantism which comprises 1173, 960, and 779 cm-1 on the IR (KBr) spectrum;administering to a patient inneed thereofan effective amountan endothermic curve comprising an endothermic peak at

of anhydrous aripiprazole crystals having low hygroscopic- about 141.5° C. in a thermogravimetric or differentiality, wherein said low hygroscopicity is defined as a moisture thermal analysis (heating rate 5° C./min); andcontent of 0.10% or less when the anhydrous aripiprazole 40 an endothermic curve comprising an endothermic peak at

crystals are placed for 24 hours in a dessicator maintained at about 140.7° C. in a differential scanning calorimetrya temperature of 60° C. and a humidity level of 100%, analysis (heating rate 5° C./min).

wherein the anhydrous aripiprazole crystals have one or 214. The method according to claim 213, wherein themore of the following properties: anhydrous aripiprazole crystals have a powder x-ray diffrac-

a powder x-ray diffraction spectrum comprising character- 45 tion spectrum comprising characteristic peaks at 20=11.00,istic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°, 16.6°, 19.3°, 20.3°, and 22.1°, using a Cu Ka x-ray.using a Cu K,, x-ray; 215. The method according to claim 213, wherein the

an infrared absorption spectrum comprising infrared anhydrous aripiprazole crystals have an infrared absorptionabsorption bands at 2945, 2812, 1678, 1627, 1448, 1377, spectrum comprising infrared absorption bands at 2945,1173, 960, and 779 cm-I on the IR (KBr) spectrum; so 2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm-I on

an endothermic curve comprising an endothermic peak at the IR (KBr) spectrum.about 141.5° C. in a thermogravimetric or differential 216. The method according to claim 213, wherein thethermal analysis (heating rate 5° C./min); and anhydrous aripiprazole crystals have an endothermic curve


about 140.7° C. in a differential scanning calorimetry 55 thermogravimetric or differential thermal analysis (heatinganalysis (heating rate 5° C./min). rate 5° C./min).

208. The method according to claim 207, wherein the 217. The method according to claim 213, wherein theanhydrous aripiprazole crystals have a powder x-ray diffrac- anhydrous aripiprazole crystals have an endothermic curve

tion spectrum comprising characteristic peaks at 20=11.0°, comprising an endothermic peak at about 140.7° C. in a

16.6°, 19.3°, 20.3°, and 22.1°, using a Cu K,, x-ray. 60 differential scanning calorimetry analysis (heating rate 5°209. The method according to claim 207, wherein the C./min).

anhydrous aripiprazole crystals have an infrared absorption 218. Amethod for the treatment ofautism which comprisesspectrum comprising infrared absorption bands at 2945, administering to a patient in need thereof from about 0.12812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm.- on milligrams to about 10 milligrams ofanhydrous aripiprazolethe IR (KBr) spectrum. 65 crystals having low hygroscopicity per 1 kg of body weight,

210. The method according to claim 207, wherein the wherein said low hygroscopicity is defined as a moistureanhydrous aripiprazole crystals have an endothermic curve content of 0.40% or less when the anhydrous aripiprazole

by USPTO from the PIRS Image Database on

08/10/2016


US 9,359,302 B2

71 72crystals are placed for 24 hours in a dessicator maintained at wherein the anhydrous aripiprazole crystals have one or

a temperature of 60° C. and a humidity level of 100%, more of the following properties:wherein the anhydrous aripiprazole crystals have a powder a powder x-ray diffraction spectrum comprising character-

x-ray diffraction spectrum which is substantially the istic peaks at 20=11.00, 16.6°, 19.3°, 20.3°, and 22.1°,same as the powder x-ray diffraction spectrum shown in 5 using a Cu Kr, x-ray;FIG. 5 using a Cu Kr, x-ray. an infrared absorption spectrum comprising infrared

219. A method for the treatment ofautism which comprises absorption bands at 2945, 2812, 1678, 1627, 1448, 1377,administering to a patient in need thereof from about 0.1 1173, 960, and 779 cm-1 on the IR (KBr) spectrum;milligrams to about 10 milligrams ofanhydrous aripiprazole an endothermic curve comprising an endothermic peak at

crystals having low hygroscopicity per 1 kg of body weight, ro about 141.5° C. in a thermogravimetric or differentialwherein said low hygroscopicity is defined as a moisture thermal analysis (heating rate 5° C./min); andcontent of 0.10% or less when the anhydrous aripiprazole an endothermic curve comprising an endothermic peak at

crystals are placed for 24 hours in a dessicator maintained at about 140.7° C. in a differential scanning calorimetrya temperature of 60° C. and a humidity level of 100%, analysis (heating rate 5° Cirnin).

wherein the anhydrous aripiprazole crystals have one or 15 226. The method according to claim 225, wherein themore of the following properties: anhydrous aripiprazole crystals have a powder x-ray diffrac-

a powder x-ray diffraction spectrum comprising character- tion spectrum comprising characteristic peaks at 20=11.0°,istic peaks at 20=11.00, 16.6°, 19.3°, 20.3°, and 22.1°, 16.6°, 19.3°, 20.3°, and 22.1°, using a Cu Kr, x-ray.using a Cu Kr, x-ray; 227. The method according to claim 225, wherein the

an infrared absorption spectrum comprising infrared 20 anhydrous aripiprazole crystals have an infrared absorptionabsorption bands at 2945, 2812, 1678, 1627, 1448, 1377, spectrum comprising infrared absorption bands at 2945,1173, 960, and 779 cm-1 on the IR (KBr) spectrum; 2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cni-1 on

an endothermic curve comprising an endothermic peak at the IR (KBr) spectrum.about 141.5° C. in a thermogravimetric or differential 228. The method according to claim 225, wherein thethermal analysis (heating rate 5° C./min); and 25 anhydrous aripiprazole crystals have an endothermic curve


about 140.7° C. in a differential scanning calorimetry thermogravimetric or differential thermal analysis (heatinganalysis (heating rate 5° C./min). rate 5° Cfrain).

220. The method according to claim 219, wherein the 229. The method according to claim 225, wherein the

anhydrous aripiprazole crystals have a powder x-ray diffrac- 30 anhydrous aripiprazole crystals have an endothermic curve

tion spectrum comprising characteristic peaks at 20=11.00, comprising an endothermic peak at about 140.7° C. in a

16.6°, 19.3°, 20.3°, and 22.1°, using a Cu Kr, x-ray. differential scanning calorimetry analysis (heating rate 5°221. The method according to claim 219, wherein the Cimin).

anhydrous aripiprazole crystals have an infrared absorption 230. Amethod for the treatmentofautismwhich comprisesspectrum comprising infrared absorption bands at 2945, 35 administering to a patient in need thereof a unit dose com-

2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm-1 on prising from about 1 milligram to about 100 milligrams ofthe IR (KBr) spectrum. anhydrous aripiprazole crystals having low hygroscopicity,

222. The method according to claim 219, wherein the wherein said low hygroscopicity is defined as a moisture

anhydrous mipiprazole crystals have an endothermic curve content of 0.40% or less when the anhydrous aripiprazolecomprising an endothermic peak at about 141.5° C. in a 40 crystals are placed for 24 hours in a dessicator maintained at

themiogravimetric or differential thermal analysis (heating a temperature of60° C. and a humidity level of 100%,rate 5° C./min). wherein the anhydrous aripiprazolecrystals have a powder

223. The method according to claim 219, wherein the x-ray diffraction spectrum which is substantially the

anhydrous aripiprazole crystals have an endothermic curve same as the powder x-ray diffraction spectrum shown in

comprising an endothermic peak at about 140.7° C. in a 45 FIG. 5 using a Cu Kr, x-ray.differential scanning calorimetry analysis (heating rate 50 231.Amethod for the treatmentofautism whichcomprisesC./min). administering to a patient in need thereof a unit dose com-

224. Amethod for the treatmentofautism which comprises prising from about 1 milligram to about 100 milligrams of

administering to a patient in need thereof from about 0.1 anhydrous aripiprazole crystals having low hygroscopicity,milligrams to about 10 milligrams ofanhydrous aripiprazole so wherein said low hygroscopicity is defined as a moisture

crystals having low hygroscopicity per 1 kg of body weight, content of 0.10% or less when the anhydrous aripiprazolewherein said low hygroscopicity is defined as a moisture crystals are placed for 24 hours in a dessicator maintained at

content of 0.10% or less when the anhydrous aripiprazole a temperature of60° C. and a humidity level of 100%,crystals are placed for 24 hours in a dessicator maintained at wherein the anhydrous aripiprazole crystals have one or

a temperature of 60° C. and a humidity level of 100%, 55 more of the following properties:wherein the anhydrous aripiprazole crystals have a powder a powder x-raydiffraction spectrum comprising character-

x-ray diffraction spectrum which is substantially the istic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°,same as the powder x-ray diffraction spectrum shown in using a Cu Ka x-ray;FIG. 5 using a Cu Kr, x-ray. an infrared absorption spectrum comprising infrared

225.A method for the treatment ofautism which comprises 60 absorption bands at 2945, 2812, 1678, 1627, 1448, 1377,administering to a patient in need thereof a unit dose com- 1173, 960, and 779 cm-1 on the IR (KBr) spectrum;prising from about 1 milligram to about 100 milligrams of an endothermic curve comprising an endothermic peak at

anhydrous aripiprazole crystals having low hygroscopicity, about 141.5° C. in a thermogravimetric or differentialwherein said low hygroscopicity is defined as a moisture thermal analysis (heating rate 5° C./min); and

content of 0.40% or less when the anhydrous aripiprazole 65 an endothermic curve comprising an endothermic peak at

crystals are placed for 24 hours in a dessicator maintained at about 140.7° C. in a differential scanning calorimetrya temperature of 60° C. and a humidity level of 100%, analysis (heating rate 5° Cimin).

Copy provided by USPTO from the MRS Image Database on


Case 1:16-cv-05400-JBS=KMW Document 1-3 Filed 09/02/16 Page 83 of 89 PagelD: 95

US 9,359,302 B273 74

232. The method according to claim 231, wherein the 240. The kit according to claim 237, wherein the anhydrousanhydrous aripiprazole crystals have a powder x-ray diffrac- aripiprazole crystals have an endothermic curve comprisingtion spectrum comprising characteristic peaks at 20=11.00, an endothermic peak at about 141.5° C. ina thermogravimet-16.6°, 19.3°, 20.3°, and 22.1°, using a Cu Ka x-ray. ric or differential thermal analysis (heating rate 5° Clmin).

233. The method according to claim 231, wherein the 5 241. The kit according to claim 237, whereinthe anhydrousanhydrous aripiprazole crystals have an infrared absorption aripiprazole crystals have an endothermic curve comprisingspectrum comprising infrared absorption bands at 2945, an endothermic peak at about 140.7° C. in a differential

2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm-1 on scanning calorimetry analysis (heating rate 5° C./min).242. A kit comprising:the IR (KBr) spectrum.

io a pharmaceutical composition comprising anhydrous arip-234. The method according to claim 231, wherein theiprazole crystals having low hygroscopicity in an

anhydrous aripiprazole crystals have an endothermic curveamount effective to treat schizophrenia and at least one

comprising an endothermic peak at about 141.5° C. in a pharmaceutically acceptable carrier, andthermogravimetric or differential thermal analysis (heating instructions for using the pharmaceutical composition torate 5° Clmin). 15 treat schizophrenia,

235. The method according to claim 231, wherein the wherein said low hygroscopicity is defined as a moistureanhydrous aripiprazole crystals have an endothermic curve content of 0.40% or less when the anhydrous aripipra-comprising an endothermic peak at about 140.7° C. in a zole crystals are placed for 24 hours in a dessicatordifferential scanning calorimetry analysis (heating rate 5° maintained at a temperature of 60° C. and a humidityCimin). 20 level of 100%,

236.Amethod for the treatmentofautism which comprises wherein the anhydrous aripiprazole crystals have a powderadministering to a patient in need thereof a unit dose com- x-ray diffraction spectrum which is substantially the

prising from about 1 milligram to about 100 milligrams of same as the powder x-ray diffraction spectrum shown in

anhydrous aripiprazole crystals having low hygroscopicity, FIG. 5 using a Cu Ka x-ray.wherein said low hygroscopicity is defined as a moisture 25 243. A kit comprising:content of 0.10% or less when the anhydrous aripiprazole a pharmaceutical composition comprising anhydrous arip-crystals are placed for 24 hours in a dessicator maintained at iprazole crystals having low hygroscopicity in an

a temperature of 60° C. and a humidity level of 100%, amount effective to treat schizophrenia and at least one

wherein the anhydrous aripiprazole crystals have a powder pharmaceutically acceptable carrier, and

x-ray diffraction spectrum which is substantially the 30 instructions for using the pharmaceutical composition to

same as the powder x-ray diffraction spectrum shown in treat schizophrenia,FIG. 5 using a Cu Ka x-ray. wherein said low hygroscopicity is defined as a moisture

237. A kit comprising: content of 0.10% or less when the anhydrous aripipra-a pharmaceutical composition comprising anhydrous arip- zole crystals are placed for 24 hours in a dessicator

iprazole crystals having low hygroscopicity in an 35 maintained at a temperature of 60° C. and a humidityamount effective to treat schizophrenia and at least one level of 100%,pharmaceutically acceptable carrier, and wherein the anhydrous aripiprazole crystals have one or

instructions for using the pharmaceutical composition to more of the following properties:treat schizophrenia, a powder x-raydiffraction spectrumcomprising character-

wherein said low hygroscopicity is defined as a moisture 40 istic peaks at 20=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°,content of0.40% or less when the anhydrous aripipra- using a Cu Ka x-ray;zole crystals are placed for 24 hours in a dessicator an infrared absorption spectrum comprising infraredmaintained at a temperature of 60° C. and a humidity absorptionbands at 2945, 2812, 1678, 1627, 1448, 1377,level of 100%, 1173, 960, and 779 cm-1 on the IR (KBr) spectrum;

wherein the anhydrous aripiprazole crystals have one or 45 an endothermic curve comprising an endothermic peak at

more of the following properties: about 141.5° C. in a thermogravimetric or differentiala powder x-ray diffraction spectrum comprising character- thermal analysis (heating rate 5° Cimin); and

istic peaks at 20=11.00, 16.6°, 19.3°, 20.3°, and 22.1°, an endothermic curve comprising an endothermic peak at

using a Cu Ka x-ray; about 140.7° C. in a differential scanning calorimetryan infrared absorption spectrum comprising infrared 50 analysis (heating rate 5° C./min).

absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 244. The kit according to claim243, whereinthe anhydrous1173, 960, and 779 crn-1 on the IR (KBr) spectrum; aripiprazole crystals have a powder x-ray diffraction spec-

an endothermic curve comprising an endothermic peak at trum comprising characteristic peaks at 26=11.00, 16.6°,about 141.5° C. in a thermogravimetric or differential 19.3°, 20.3°, and 22.1°, using a Cu Ka x-ray.thermal analysis (heating rate 5° CJmin); and 55 245. The kit accordingto claim243, whereinthe anhydrous

an endothermic curve comprising an endothermic peak at aripiprazole crystals have an infrared absorption spectrumabout 140.7° C. in a differential scanning calorimetry comprising infrared absorption bands at 2945, 2812, 1678,analysis (heating rate 5° Clmin). 1627, 1448, 1377, 1173, 960, and 779 cm-1 on the IR (KBr)

238. Thekit according to claim 237, wherein the anhydrous spectrum.aripiprazole crystals have a powder x-ray diffraction spec- 60 246. The kit accordingto claim 243, whereinthe anhydroustram comprising characteristic peaks at 20=11.0°, 16.6°, aripiprazole crystals have an endothermic curve comprising19.3°, 20.3°, and 22.1°, using a Cu lc x-ray. an endothermic peak at about 141.5° C. ina thermogravimet-

239. The kit according to claim 237, wherein the anhydrous ric or differential thermal analysis (heating rate 5° Cimin).aripiprazole crystals have an infrared absorption spectrum 247. The kitaccording to claim 243, whereinthe anhydrouscomprising infrared absorption bands at 2945, 2812, 1678, 65 aripiprazole crystals have an endothermic curve comprising1627, 1448, 1377, 1173, 960, and 779 cm-1 on the IR (KBr) an endothermic peak at about 140.7° C. in a differential

spectrum. scanning calorimetry analysis (heating rate 5° C./min).



US 9,359,302 B2

75 76248. A kit comprising: ofsaid Anhydrous Aripiprazole Crystals B in a 20 mLn-hex-a pharmaceutical composition comprising anhydrous arip- ane solution of0.5 g soy lecithin.

iprazole crystals having low hygroscopicity in an 261. AnhydrousAripiprazole Crystals B having low hygro-amount effective to treat schizophrenia and at least one scopicity prepared by a process comprising heating Hydratepharmaceutically acceptable carrier, and 5 A ofaripiprazole,

instructions for using the pharmaceutical composition to wherein said low hygroscopicity is defined as a moisturetreat schizophrenia, content of0.40% or less when the Anhydrous Aripipra-

wherein said low hygroscopicity is defined as a moisture zole Crystals B are placed for 24 hours in a dessicatorcontent of 0.10% or less when the anhydrous aripipra- maintained at a temperature of 60° C. and a humidityzole crystals are placed for 24 hours in a dessicator 10 level of 100%.maintained at a temperature of 60° C. and a humidity 262. The Anhydrous Aripiprazole Crystals B according to

level of 100%, claim 261, whereinsaid process comprises heating Hydrate Awherein the anhydrous aripiprazole crystals have a powder ofaripiprazole at 90-125° C. for about 3-50 hours.

x-ray diffraction spectrum which is substantially the 263. The Anhydrous Aripiprazole Crystals B according to

same as the powder x-ray diffraction spectrum shown in 15 claim 261, wherein said process comprises heating Hydrate AFIG. 5 using a Cu Ka x-ray. ofaripiprazole at 100° C. for about 18 hours.

249. AnhydrousAripiprazole Crystals B having low hygro- 264. The Anhydrous Aripiprazole Crystals B according to

scopicity, wherein said low hygroscopicity is defined as a claim261, wherein said process comprisesheating Hydrate Amoisture content of0.40% or less when the Anhydrous Arip- ofaripiprazole at 100° C. for about 24 hours.

iprazole Crystals B are placed for 24 hours in a dessicator 20 265. The Anhydrous Aripiprazole Crystals B according tomaintained at a temperature of 60° C. and a humidity level of claim 261, wherein said process comprisesheating Hydrate A

100%, ofaripiprazole at 120° C. for about 3 hours.wherein the Anhydrous Aripiprazole Crystals B have a 266. TheAnhydrous Aripiprazole Crystals B according to

mean particle size of 50 pm or less. claim261, wherein said process comprisesheating HydrateA250. The Anhydrous Aripiprazole Crystals B according to 25 of aripiprazole for about 18 hours at 100° C. followed by

claim 249, wherein the mean particle size is measured using additional heating for about 3 hours at 120° C.a laser diffraction particle size analyzer. 267. AnhydrousAripiprazole Crystals B having low hygro-

251. The Anhydrous Aripiprazole Crystals B according to scopicity prepared by a process comprising heating Hydrateclaim 249, wherein the mean particle size is measured using A ofaripiprazole,a laser diffraction particle size analyzer by suspending 0.1 g 30 wherein said low hygroscopicity is defined as a moistureofsaid Anhydrous Aripiprazole Crystals B in a 20 mL n-hex- content of0.10% or less when the Anhydrous Aripipra-ane solution of0.5 g soy lecithin. zole Crystals B are placed for 24 hours in a dessicator

252. The Anhydrous Aripiprazole Crystals B according to maintained at a temperature of 60° C. and a humidityclaim 249, wherein the Anhydrous Aripiprazole Crystals B level of 100%.have a mean particle size of 30 pm or less. 35 268. TheAnhydrous Aripiprazole Crystals B according to

253. The Anhydrous Aripiprazole Crystals B according to claim267, wherein said process comprises heating HydrateAclaim 252, wherein the mean particle size is measured using ofaripiprazole at 90-125° C. for about 3-50 hours.a laser diffraction iiarticle size analyzer. 269. The Anhydrous Aripiprazole Crystals B according to

254. The Anhydrous Aripiprazole Crystals B according to claim 267, whereinsaid process comprisesheating Hydrate Aclaim 252, wherein the mean particle size is measured using ao ofaripiprazole at 100° C. for about 18 hours.a laser diffraction particle size analyzer by suspending 0.1 g 270. The Anhydrous Aripiprazole Crystals B according to

ofsaid Anhydrous Aripiprazole Crystals B in a 20 mL n-hex- claim 267, whereinsaid process comprisesheating Hydrate Aane solution of 0.5 g soy lecithin, ofaripiprazole at 100° C. for about 24 hours.

255. AnhydrousAripiprazole Crystals B having low hygro- 271. TheAnhydrous Aripiprazole Crystals B according to

scopicity, wherein said low hygroscopicity is defined as a 45 claim267, wherein said process comprises heating HydrateAmoisture content of0.10% or less when theAnhydrous Arip- ofaripiprazole at 120° C. for about 3 hours.

iprazole Crystals B are placed for 24 hours in a dessicator 272. TheAnhydrous Aripiprazole Crystals B according to

maintained at a temperature of60° C. and a humidity level of claim 267, whereinsaid process comprisesheating HydrateA100%, wherein theAnhydrous Aripiprazole Crystals B have a of aripiprazole for about 18 hours at 100° C. followed bymean particle size of 50 pm or less. so additional heating for about 3 hours at 120° C.

256. The Anhydrous Aripiprazole Crystals B according to 273. A pharmaceutical composition comprising Anhy-claim 255, wherein the mean particle size is measured using drous Aripiprazole Crystals B having low hygroscopicity anda laser diffraction particle size analyzer. at least one pharmaceutically acceptable carrier,

257. The Anhydrous Aripiprazole Crystals B according to wherein said low hygroscopicity is defined as a moistureclaim 255, wherein the mean particle size is measured using 55 content of0.40% or less when the Anhydrous Aripipra-a laser diffraction particle size analyzer by suspending 0.1 g zole Crystals B are placed for 24 hours in a dessicatorofsaid Anhydrous Aripiprazole Crystals B in a 20 mL n-hex- maintained at a temperature of 60° C. and a humidityane solution of0.5 g soy lecithin, level of 100%.

258. The Anhydrous Aripiprazole Crystals B according to 274. The pharmaceutical composition according to claimclaim 255, wherein the Anhydrous Aripiprazole Crystals B 60 273, wherein said pharmaceutical composition compriseshave a mean particle size of 30 pm or less. said Anhydrous Aripiprazole Crystals B in an amount effec-

259. The Anhydrous Aripiprazole Crystals B according to tive to treat schizophrenia.claim 258, wherein the mean particle size is measured using 275. The pharmaceutical composition according to claima laser diffraction particle size analyzer. 273, wherein said pharmaceutical composition is in the form

260. The Anhydrous Aripiprazole Crystals B according to 65 ofa solid oral tablet.claim 258, wherein the mean particle size is measured using 276. The pharmaceutical composition according to claima laser diffraction particle size analyzer by suspending 0.1 g 275, wherein said solid oral tablet has at least one dissolution

Copy provided by USPTO from the P1RS Image Database on 0811012016

Copy provided by USPTO from 0/2016


US 9,359,302 B277 78

rate selected from the group consisting of60% or more at pH 288. A method for the treatment of schizophrenia which4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes, comprises administering to a patient in need thereof fromand 55% or more at pH 5.0 after 60 minutes. about 0.1 milligrams to about 10 milligrams of Anhydrous

277. The pharmaceutical composition according to claim Aripiprazole Crystals B having low hygroscopicity per 1 kg273, wherein said pharmaceutical composition is in the form s ofbody weight,of an oral flashmelt tablet. wherein said low hygroscopicity is defined as a moisture

278. The pharmaceutical composition according to claim content of0.10% or less when the Anhydrous Aripipra-277, wherein said oral flashmelt tablet has at least one disso- zole Crystals B are placed for 24 hours in a dessicatorlution rate selected from the group consisting of60% or more maintained at a temperature of 60° C. and a humidityat pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 to level of 100%.minutes, and 55% or more at pH 5.0 after 60 minutes.

289. A method for the treatment of schizophrenia which279. A pharmaceutical composition comprising Anhy- comprises administering to a patient in need thereof a unitdrousAripiprazole Crystals B having low hygroscopicity anddose comprising from about 1 milligram to about 100 milli-.at least one pharmaceutically acceptable carrier,

wherein said low hygroscopicity is defined as a moisture is grams of Anhydrous Aripiprazole Crystals B having low

content of 0.10% or less when the Anhydrous Aripipra- hygroscopicity,zole Crystals B are placed for 24 hours in a dessicator wherein said low hygroscopicity is defined as a moisturemaintained at a temperature of 60° C. and a humidity content of0.40% or less when the Anhydrous Aripipra-level of 100%. zole Crystals B are placed for 24 hours in a dessicator

280. The pharmaceutical composition according to claim 20 maintained at a temperature of 60° C. and a humidity279, wherein said pharmaceutical composition comprises level of 100%.said Anhydrous Aripiprazole Crystals B in an amount effec- 290. A method for the treatment of schizophrenia whichtive to treat schizophrenia. comprises administering to a patient in need thereof a unit

281. The pharmaceutical composition according to claim dose comprising from about 1 milligram to about 100 milli-279, wherein said pharmaceutical composition is in the form 25 grams of Anhydrous Aripiprazole Crystals B having lowof a solid oral tablet. hygroscopicity,

282. The pharmaceutical composition according to claim wherein said low hygroscopicity is defined as a moisture281, wherein said solid oral tablet has at least one dissolution content of 0.10% or less when the Anhydrous Aripipra-rate selected fromthe group consisting of60% or more at pH zole Crystals B are placed for 24 hours in a dessicator4.5 after 30 minutes, 70% ormore at pH 4.5 after 60 minutes, 30 maintained at a temperature of 60° C. and a humidityand 55% or more at pH 5.0 after 60 minutes. level of 100%.

283. The pharmaceutical composition according to claim291. A method for the treatment ofbipolar disorder which

279, wherein said pharmaceutical composition is in the formcomprises administering to a patient in need thereofan effec-of an oral flashmelt tablet.tive amount ofAnhydrousAripiprazole Crystals B having low284. The pharmaceutical composition according to claim 35

283, wherein said oral flashmelt tablet has at least one disso- hygroscopicity,lution rate selected from the group consisting of60% or more wherein said low hygroscopicity is defined as a moisture

at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 content of 0.40% or less when theAnhydrous Aripipra-minutes, and 55% or more at pH 5.0 after 60 minutes. zole Crystals B are placed for 24 hours in a dessicator

285. A method for the treatment of schizophrenia which ao maintained at a temperature of 60° C. and a humiditycomprises administering to a patient inneed thereofan effec- level of 100%.five amount ofAnhydrousAripiprazole Crystals B having low 292. A method for the treatment ofbipolar disorder whichhygroscopicity, comprises administering to a patient in need thereofan effec-

wherein said low hygroscopicity is defined as a moisture tive amount ofAnhydrousAripiprazole Crystals B having lowcontent of0.40% or less when the Anhydrous Aripipra- 45 hygroscopicity,zole Crystals B are placed for 24 hours in a dessicator wherein said low hygroscopicity is defined as a moisturemaintained at a temperature of 60° C. and a humidity content of 0.10% or less when the Anhydrous Aripipra-level of 100%. zole Crystals B are placed for 24 hours in a dessicator

286. A method for the treatment of schizophrenia which maintained at a temperature of 60° C. and a humiditycomprises administering to a patient inneed thereofan effec- 50 level of 100%.fiveamount ofAnhydrousAripiprazole Crystals B having low 293. A method for the treatment ofbipolar disorder whichhygroscopicity, comprises administering to a patient in need thereof from

wherein said low hygroscopicity is defined as a moisture about 0.1 milligrams to about 10 milligrams ofAnhydrouscontent of0.10% or less when the Anhydrous Aripipra- Aripiprazole Crystals B having low hygroscopicity per 1 kgzole Crystals B are placed for 24 hours in a dessicator 55 ofbody weight,maintained at a temperature of 60° C. and a humidity wherein said low hygroscopicity is defined as a moisturelevel of 100%. content of0.40% or less when the Anhydrous Aripipra-

287. A method for the treatment of schizophrenia which zole Crystals B are placed for 24 hours in a dessicatorcomprises administering to a patient in need thereof from maintained at a temperature of 60° C. and a humidityabout 0.1 milligrams to about 10 milligrams of Anhydrous 60 level of 100%.Aripiprazole Crystals B having low hygroscopicity per 1 kg 294. A method for the treatment ofbipolar disorder whichof body weight, comprises administering to a patient in need thereof from

wherein said low hygroscopicity is defined as a moisture about 0.1 milligrams to about 10 milligrams of Anhydrouscontent of0.40% or less when the Anhydrous Aripipra- Aripiprazole Crystals B having low hygroscopicity per 1 kgzole Crystals B are placed for 24 hours in a dessicator 65 ofbody weight,maintained at a temperature of 60° C. and a humidity wherein said low hygroscopicity is defined as a moisturelevel of 100%. content of0.10% or less when the Anhydrous Aripipra-

the PIKS Image Database on 08/1

Copy provided by


US 9,359,302 B279 80

zole Crystals B are placed for 24 hours in a dessicator wherein said low hygroscopicity is defined as a moisturemaintained at a temperature of 60° C. and a humidity content of0.40% or less when the Anhydrous Aripipra-level of 100%. zole Crystals B are placed for 24 hours in a dessicator

295. A method for the treatment ofbipolar disorder which maintained at a temperature of 60° C. and a humiditycomprises administering to a patient in need thereof a unit 5 level of 100%.dose comprising from about 1 milligram to about 100 milli- 302. A method for the treatment ofanxiety, depression, or

grams of Anhydrous Aripiprazole Crystals B having low mania which comprises administering to a patient in need

hygroscopicity, thereof a unit dose comprising from about 1 milligram to

wherein said low hygroscopicity is defined as a moisture about 100 milligrams ofAnhydrous Aripiprazole Crystals Bcontent of0.40% or less when the Anhydrous Aripipra- 10 having low hygroscopicity,zole Crystals B are placed for 24 hours in a dessicator wherein said low hygroscopicity is defined as a moisturemaintained at a temperature of 60° C. and a humidity content of0.10% or less when the Anhydrous Aripipra-level of 100%. zole Crystals B are placed for 24 hours in a dessicator

296.A method for the treatment ofbipolar disorder which15

maintained at a temperature of 60° C. and a humiditycomprises administering to a patient in need thereof a unit level of 100%.dose comprising from about 1 milligram to about 100 milli- 303. Amethod for the treatment ofautismwhich comprisesgrams of Anhydrous Aripiprazole Crystals B having low administering to a patient in need thereofan effective amount

hygroscopicity, ofAnhydrousAripiprazo le Crystals B having low hygroscop-wherein said low hygroscopicity is defined as a moisture 20 icity,

content of0.10% or less when the Anhydrous Aripipra- wherein said low hygroscopicity is defined as a moisturezole Crystals B are placed for 24 hours in a dessicator content of0.40% or less when the Anhydrous Aripipra-maintained at a temperature of 60° C. and a humidity zole Crystals B are placed for 24 hours in a dessicatorlevel of 100%. maintained at a temperature of 60° C. and a humidity

297. A method for the treatment ofanxiety, depression, or 25 level of 100%.mania which comprises administering to a patient in need 304.Amethod for the treatment ofautismwhich comprisesthereofan effective amount ofAnhydrous Aripiprazole Crys- administering to a patient inneed thereofan effective amounttals B having low hygroscopicity, ofAnhydrousAripiprazole Crystals B having low hygroscop-wherein said low hygroscopicity is defined as a moisture icity,

content of0.40% or less when the Anhydrous Aripipra- 30 wherein said low hygroscopicity is defined as a moisturezole Crystals B are placed for 24 hours in a dessicatorcontent of0.10% or less when theAnhydrous Aripipra-maintained at a temperature of 60° C. and a humidity

ll a100%zoleCrystals B are placed for 24 hours hi a dessicatoreve.

maintained at a temperature of 60° C. and a humidity298.A method for the treatment ofanxiety, depression, or

mania which comprises administering to a patient in need 35level of 100%.

305. Amethod for the treatment ofautismwhich comprisesthereofan effective amount ofAnhydrous Aripiprazole Crys-tals B having low hygroscopicity, administering to a patient in need thereof from about 0.1

wherein said low hygroscopicity is defined as a moisture milligrams to about 10 milligrams ofAnhydmusAripiprazolecontent of0.10% or less when the Anhydrous Aripipra- Crystals B having low hygroscopicity per 1 kg of bodyzole Crystals B are placed for 24 hours in a dessicator 40 weight,maintained at a temperature of 60° C. and a humidity wherein said low hygroscopicity is defined as a moisturelevel of 100%. content of0.40% or less when the Anhydrous Aripipra-

299. A method for the treatment of anxiety, depression, or zole Crystals B are placed for 24 hours in a dessicatormania which comprises administering to a patient in need maintained at a temperature of 60° C. and a humiditythereof from about 0.1 milligrams to about 10 milligrams of 45 level of 100%.Anhydrous Aripiprazole Crystals B having low hygroscopic- 306.A method forthe treatment ofautismwhich comprisesity per 1 kg ofbody weight, administering to a patient in need thereof from about 0.1

wherein said low hygroscopicity is defined as a moisture milligrams to about 10 milligrams ofAnhydrousAripiprazolecontent of0.40% or less when the Anhydrous Aripipra- Crystals B having low hygroscopicity per 1 kg of bodyzole Crystals B are placed for 24 hours in a dessicator so weight,maintained at a temperature of 60° C. and a humidity wherein said low hygroscopicity is defined as a moisturelevel of 100%. content of0.10% or less when the Anhydrous Aripipra-

300. A method for the treatment ofanxiety, depression, or zole Crystals B are placed for 24 hours in a dessicatormania which comprises administering to a patient in need maintained at a temperature of 60° C. and a humiditythereoffrom about 0.1 milligrams to about 10 milligrams of 55 level of 100%.Anhydrous Aripiprazole Crystals B having low hygroscopic- 307. Amethod for the treatmentofautism whichcomprisesity per 1 kg ofbody weight, administering to a patient in need thereof a unit dose corn-

wherein said low hygroscopicity is defined as a moisture prising from about 1 milligram to about 100 milligrams ofcontent of 0.10% or less when the Anhydrous Aripipra- Anhydrous Aripiprazole Crystals B having low hygroscopic-zole Crystals B are placed for 24 hours in a dessicator 60 ity,maintained at a temperature of 60° C. and a humidity wherein said low hygroscopicity is defined as a moisturelevel of 100%. content of0.40% or less when the Anhydrous Aripipra-

301. A method for the treatment of anxiety, depression, or zole Crystals B are placed for 24 hours in a dessicatormania which comprises administering to a patient in need maintained at a temperature of 60° C. and a humiditythereof a unit dose comprising from about 1 milligram to 65 level of 100%.about 100 milligrams ofAnhydrous Aripiprazole Crystals B 308. Amethod for the treatment ofautismwhich compriseshaving low hygroscopicity, administering to a patient in need thereof a unit dose com-

USPTO from the PIRS Image Database on 08/10/2016

Copy provided by USPTO from the

Case 1:16-cv-05400-JBS-KMW Document 1-3 Filed 09/02/16 Page 87

US 9,359,302 B281 82

prising from about 1 milligram to about 100 milligrams ofAnhydrous Aripiprazole Crystals B having low hygroscopic-ity,

wherein said low hygroscopicity is defmed as a moisturecontent of 0.10% or less when the Anhydrous Aripipra- 5zole Crystals B are placed for 24 hours in a dessicatormaintained at a temperature of 60° C. and a humiditylevel of 100%.

309. A kit comprising:a pharmaceutical composition comprising Anhydrous to

Aripiprazole Crystals B having low hygroscopicity inan

amount effective to treat schizophrenia and at least one

pharmaceutically acceptable carrier, and 1instructions for using the pharmaceutical composition to

treat schizophrenia, 15wherein said low hygroscopicity is defined as a moisture

content of 0.40% or less when the Anhydrous Aripipra-zole Crystals B are placed for 24 hours in a dessicatormaintained at a temperature of 60° C. and a humiditylevel of 100%. 20

310. A kit comprising:a pharmaceutical composition comprising Anhydrous

Aripiprazole Crystals B having low hygroscopicity in an

amount effective to treat schizophrenia and at least one

pharmaceutically acceptable carrier, and 25instructions for using the pharmaceutical composition to

treat schizophrenia,wherein said low hygroscopicity is defined as a moisture

content of0.10% or less when the Anhydrous Aripipra-zole Crystals B are placed for 24 hours in a dessicator 30

maintained at a temperature of 60° C. and a humiditylevel of 100%.

PIRS Image Database on 08/10/2016

of 819-PagetD799

-i


1.•,

•••••-•-1-•.: .•::.-•e•.%, 'Ir. :::•-n.., r •••'-'4"....: I.--, I,

m;;••:•-'-'''-..- -.7.4tk.'-'-:•-, ii...-••••:.••••••*;.......,, .'.....--...::.:!..:-.•.4t.--:•=--..:••P• •-'1,

sr. ;•••••;E-i:-.1.fi--...., •!.5[-.Js.:::••..-..-,..;:•;:.?...A.A:,, :-:.17 :::.-2.?.!-;:-:: -7-.':', 0•:.: f-, ....-r..:,

.i.. -.--.1,-.-:i.i-,=.4..,,:_t•-;:g,V., ---Fif .4-:::, ..4%;, 1-...4...?...-:.-..-...-4::•L---.,,,A,74-,,

-:-.4, •*-‘:•1&.- e'".---,,f --'-k'-:, 1-...:-...•;;--4, ..t. -a-.. •••-....:7 ......--x.::;lt...,,,I....,, .--..--.•-•;.;iiz•-..-...3f:•:.:;:.:.-.::,,.5..f..---.-t.. 1-. --Az-•-=----._t-----f. .:4...;.,_04:--.1..-if.--.:.....f7-,. -L:Y) -...k ..5.-?•'..:.-..-1..--.,; 2.'-----=-1. 1 ..-4)::.. xv--7.-Si. e- --t.-,-.-•_4;..-t-. N-z, F...\:.' r.w- -.Ft n-l+R.-.: •:-'.7.-.-:,

-%••.':.0-7.. ....7-1-.....„-17-W' .--.-744.;; •t-.5, :-f

-.T--ir-..If.-1 ..;e-..-.....- .i'lt-•••4.,,,,.--7_-......4_.4--, ..T--....-• .4.. ii.., -4..., 41-

r,

.:Y.-, .:.';'.'...-•••::"'4'.,:i:',


PTO-1683

(Rev. 7-96)